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Abstract:

This invention relates to compounds of the Formula (I)-(IX):, as defined
herein, or a pharmaceutically acceptable salt, solvate or ester thereof,
which can be useful for the treatment of diseases or conditions mediated
by MMPs, ADAMs, TACE, aggrecanase, TNF-α combinations thereof.
##STR00001## ##STR00002##

Claims:

1. A compound represented by Formula (I): ##STR00142## or a
pharmaceutically acceptable salt thereof, wherein: ring A is aryl or
heteroaryl, wherein said aryl or heteroaryl is unsubstituted or
substituted with R2 or --OR3, wherein R2 is H or halo, and
R3 is H or alkyl; T is aryl or heteroaryl, substituted with an
R4, R5, and R6 as shown; X is selected from the group
consisting of --S--, --O--, --S(O)2--, --S(O)--,
--(CR.sup.8.sub.2)p-- and --N(R')--; p is 1 to 3; R' is selected
from the group consisting of H, alkyl, and aryl; R is selected from the
group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl,
heterocyclenyl, aryl, heteroaryl, --C(═O)alkyl,
--C(═O)cycloalkyl, --C(═O)heterocyclyl, --C(═O)aryl,
--C(═O)heteroaryl, --C(═O)O-alkyl, --C(═O)O-cycloalkyl,
--C(═O)O-heterocyclyl, --C(═O)O-aryl, and
--C(═O)O-heteroaryl; R1 is selected from the group consisting of
H and --C(R7)2-(Q)nR9; R4 is selected from the
group consisting of H, alkyl, and halogen; R5 and R6 are
substituents on adjacent carbon atoms, wherein R5 and R6
together with the carbon atoms to which they are attached form a first
five- to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or
heterocyclenyl; wherein said first five- to eight-membered cycloalkyl,
cycloalkenyl, heterocyclyl, or heterocyclenyl contains two radicals on
the same carbon atom, and said radicals taken together with the carbon
atom to which they are attached form a second five- to eight-membered
cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl; wherein said
first five- to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or
heterocyclenyl, optionally with said second five- to eight-membered
cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl is
unsubstituted or substituted with one to four R10 moieties; each
R7 independently is selected from the group consisting of H, alkyl,
and aryl; each R8 independently is selected from the group
consisting of H, alkyl, and aryl; R9 is selected from the group
consisting of H, alkyl, heterocyclyl, aryl, heteroaryl,
--C(═O)N(R12)2, --C(═O)-alkyl, C(═O)-cycloalkyl,
C(═O)-heterocyclyl, --C(═O)-aryl, --C(═O)-heteroaryl,
--C(═O)--O-alkyl, --C(═O)--O-cycloalkyl,
--C(═O)--O-heterocyclyl, --C(═O)--O-aryl,
--C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; each R10 is independently selected
from the group consisting of cyano, nitro, --OC(O)R11,
--C(R11)═N--OR11, --OR11, --SR11,
--N(R11)2, --S(O)R11, --S(O)2R11,
--N(R11)S(O)2R11, --N(R11)--C(O)--R11,
--N(R11)--C(O)--N(R11)2, --N(R11)--C(O)--OR11,
--OC(O)N(R11)2, --C(O)N(R11)--S(O)2R11,
--S(O)2N(R11)--C(O)--R11, --C(O)N(R11)C(O)R11,
--C(O)N(R11)C(O)NR11, --S(O)2N(R11)2,
--N(R11)--C(═NR11)--N(R11)2,
--N(R11)--C(═N--CN)--N(R11)2, -haloalkoxy,
--C(O)OR11, --C(O)R11, --C(O)N(R11)2, halogen, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkenyl,
and cycloalkyl, with the proviso that there are no adjacent heteroatoms
in any of said R10; each R11 independently is selected from the
group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy,
heterocyclyl, aryl, and heteroaryl; Q is selected from the group
consisting of --NR12--, --O--, --S--, --S(O)--, and --S(O)2--,
each R12 is independently selected from the group consisting of H
and alkyl; and n is 0 or 1.

2. The compound of claim 1, selected from the group consisting of:
##STR00143## ##STR00144## or a pharmaceutically acceptable salt
thereof.

3. A compound represented by Formula (II) ##STR00145## or a
pharmaceutically acceptable salt thereof, wherein: T is aryl or
heteroaryl, each of which is substituted with m R5 substituents as
shown; X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR.sup.6.sub.2)p-- and --N(R')--; p is
1 to 3; R' is selected from the group consisting of H, alkyl, and aryl; R
is selected from the group consisting of H, alkyl, cycloalkyl,
cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,
--C(═O)alkyl, --C(═O)cycloalkyl, --C(═O)heterocyclyl,
--C(═O)aryl, --C(═O)heteroaryl, --C(═O)O-alkyl,
--C(═O)O-cycloalkyl, --C(═O)O-heterocyclyl, --C(═O)O-aryl,
and --C(═O)O-heteroaryl; R1 is selected from the group
consisting of H and --C(R6)2-(Q)nR7; R2 is
selected from the group consisting of H, alkyl, and halogen; R3 and
R4 are substituents on adjacent carbon atoms, wherein R3 and
R4 together with the carbon atoms to which they are attached form a
first five or six-membered heteroaryl, which is unsubstituted or
substituted with one or two substituents independently selected from the
group consisting of alkyl and cycloalkyl; R5 is selected from the
group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R6 independently is selected from the group consisting of H,
alkyl, and aryl; R7 is selected from the group consisting of H,
alkyl, heterocyclyl, aryl, heteroaryl, --C(═O)N(R8)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; each R8 is independently selected
from the group consisting of H and alkyl; Q is selected from the group
consisting of --NR8--, --O--, --S--, --S(O)--, and --S(O)2--; n
is 0 or 1; and m is 0-3.

4. The compound of claim 3, selected from the group consisting of:
##STR00146## or a pharmaceutically acceptable salt thereof.

5. A compound represented by Formula (III) ##STR00147## or a
pharmaceutically acceptable salt thereof, wherein: ring B is aryl or
heteroaryl, wherein said aryl or heteroaryl is unsubstituted or
substituted with alkoxy; at least one of T and V is present; T is absent
or present, and if present, is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl,
heterocyclenyl, and heteroaryl; V is absent or present, and if present,
is selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and
heteroaryl; R is selected from the group consisting of H, alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,
--C(═O)alkyl, --C(═O)cycloalkyl, --C(═O)heterocyclyl,
--C(═O)aryl, --C(═O)heteroaryl, --C(═O)O-alkyl,
--C(═O)O-cycloalkyl, --C(═O)O-heterocyclyl, --C(═O)O-aryl,
and --C(═O)O-heteroaryl; R1 is selected from the group
consisting of H and --C(R3)2-(Q)nR4; each R3
independently is selected from the group consisting of H, alkyl and aryl;
R4 is selected from the group consisting of H, alkyl, heterocyclyl,
aryl, heteroaryl, --C(═O)N(R5)2, --C(═O)-alkyl,
C(═O)-cycloalkyl, C(═O)-heterocyclyl, --C(═O)-aryl,
--C(═O)-heteroaryl, --C(═O)--O-alkyl, --C(═O)--O-cycloalkyl,
--C(═O)--O-heterocyclyl, --C(═O)--O-aryl,
--C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; Q is selected from the group consisting
of --NR5--, --O--, --S--, --S(O)--, and --S(O)2--; each R5
is independently selected from the group consisting of H and alkyl; and n
is 0 or 1.

6. The compound of claim 5, selected from the group consisting of:
##STR00148## or a pharmaceutically acceptable salt thereof.

7. A compound represented by Formula (IV): ##STR00149## or a
pharmaceutically acceptable salt thereof, wherein: ring A is aryl or
heteroaryl, substituted on adjacent ring atoms with R2, R3, and
R4; at least one of T and V is present; T is absent or present, and
if present, is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl,
and heteroaryl; V is absent or present, and if present, is selected from
the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl; X is
selected from the group consisting of --S--, --O--, --S(O)2--,
--S(O)--, --(CR.sup.5.sub.2)p-- and --N(R')--; p is 1 to 3; R' is
selected from the group consisting of H, alkyl, and aryl; R is selected
from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, aryl, heteroaryl, --C(═O)alkyl,
--C(═O)cycloalkyl, --C(═O)heterocyclyl, --C(═O)aryl,
--C(═O)heteroaryl, --C(═O)O-alkyl, --C(═O)O-cycloalkyl,
--C(═O)O-heterocyclyl, --C(═O)O-aryl, and
--C(═O)O-heteroaryl; R1 is selected from the group consisting of
H and --C(R6)2-(Q)nR7; R2, R3, and R4
are substituents on adjacent ring atoms, wherein each of R2,
R3, and R4 is independently selected from the group consisting
of halo, alkyl, and alkoxy; each R5 independently is selected from
the group consisting of H, alkyl, and aryl; each R6 independently is
selected from the group consisting of H, alkyl, and aryl; R7 is
selected from the group consisting of H, alkyl, heterocyclyl, aryl,
heteroaryl, --C(═O)N(R8)2, --C(═O)-alkyl,
C(═O)-cycloalkyl, C(═O)-heterocyclyl, --C(═O)-aryl,
--C(═O)-heteroaryl, --C(═O)--O-alkyl, --C(═O)--O-cycloalkyl,
--C(═O)--O-heterocyclyl, --C(═O)--O-aryl,
--C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; Q is selected from the group consisting
of --NR8--, --O--, --S--, --S(O)--, and --S(O)2--; each R8
is independently selected from the group consisting of H and alkyl; and n
is 0 or 1.

8. The compound of claim 7, selected from the group consisting of:
##STR00150## ##STR00151## a pharmaceutically acceptable salt thereof.

9. A compound represented by Formula (V): ##STR00152## or a
pharmaceutically acceptable salt thereof, wherein: ring A is aryl or
heteroaryl, wherein said aryl or heteroaryl is unsubstituted or
substituted with alkoxy or deuterium; at least one of T and V is present,
and at least one of T and V is substituted with 1-3 R2 substituents;
T is absent or present, and if present is selected from the group
consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl; V is absent or present, and
if present is selected from the group consisting of: alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl,
and heteroaryl; X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR.sup.7.sub.2)p-- and --N(R')--; p is
1 to 3; R' is selected from the group consisting of H, alkyl, and aryl; R
is selected from the group consisting of H, alkyl, cycloalkyl,
cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,
--C(═O)alkyl, --C(═O)cycloalkyl, --C(═O)heterocyclyl,
--C(═O)aryl, --C(═O)heteroaryl, --C(═O)O-alkyl,
--C(═O)O-cycloalkyl, --C(═O)O-heterocyclyl, --C(═O)O-aryl,
and --C(═O)O-heteroaryl; R1 is selected from the group
consisting of H and --C(R6)2-(Q)nR9, Q is selected
from the group consisting of --NR6--, --O--, --S--, --S(O)--, and
--S(O)2--; and n is 0 or 1. R2 is selected from the group
consisting of deuterium, --C(═N--OH)--N(R6)2,
--C(═O)NR6S(═O)2N(R6)2,
--C(R6)((C═O)OR6)-heterocyclyl-C(═O)OR6,
--C(R6)((C═O)N(R6)2)-heterocyclyl-C(═O)Oalkyl,
--C(═NR6)--N(R6)OR6,
--C(═NR6)--N(R6)-heterocyclyl,
--C(═NR6)--N(R6)-aryl,
--C(═NR6)--N(R6)-heteroaryl,
--C(═NR6)--N(R6)2, and
--NR6--C(═S)N(R6)-alkyl-heterocyclyl; each R6
independently is H or alkyl; each R7 independently is H, alkyl, or
aryl; R9 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R6)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring.

10. The compound of claim 9, selected from the group consisting of:
##STR00153## ##STR00154## ##STR00155## ##STR00156## or a
pharmaceutically acceptable salt thereof.

11. A compound represented by Formula (VI): ##STR00157## or a
pharmaceutically acceptable salt thereof; wherein: ring A is aryl or
heteroaryl, where said aryl or heteroaryl is unsubstituted or is
substituted with one or two substituents selected from the group
consisting of halo and alkoxy; X is selected from the group consisting of
--S--, --O--, --S(O)2--, --S(O)--, --(CR.sup.7.sub.2)p-- and
--N(R')--; p is 1 to 3; Y is O or S; T is aryl or heteroaryl; R' is
selected from the group consisting of H, alkyl, and aryl; R is selected
from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, aryl, heteroaryl, --C(═O)alkyl,
--C(═O)cycloalkyl, --C(═O)heterocyclyl, --C(═O)aryl,
--C(═O)heteroaryl, --C(═O)O-alkyl, --C(═O)O-cycloalkyl,
--C(═O)O-heterocyclyl, --C(═O)O-aryl, and
--C(═O)O-heteroaryl; R1 is selected from the group consisting of
H and --C(R6)2-(Q)nR9, Q is selected from the group
consisting of --NR6--, --O--, --S--, --S(O)--, and --S(O)2--, n
is 0 or 1; each of R1 and R2 is independently H or alkyl; each
of R4 and R5 is independently selected from the group
consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
or wherein R4 and R5 together with the nitrogen atom to which
they are shown attached form a heterocyclyl or heteroaryl ring; each
R6 independently is H or alkyl; each R7 independently is H,
alkyl or aryl; and R9 is selected from the group consisting of H,
alkyl, heterocyclyl, aryl, heteroaryl, --C(═O)N(R6)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring.

12. The compound of claim 11, selected from the group consisting of:
##STR00158## or a pharmaceutically acceptable salt thereof.

13. A compound represented by Formula (VII): ##STR00159## or a
pharmaceutically acceptable salt thereof; wherein: ring A is aryl,
wherein said aryl is unsubstituted or substituted with alkoxy; T is
heteroaryl, wherein when said T heteroaryl contains two radicals on
adjacent carbon atoms, said radicals may optionally be taken together
with the carbon atoms to which they are attached to form a five- to eight
membered heterocyclyl ring; R is selected from the group consisting of H,
alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl,
heteroaryl, --C(═O)alkyl, --C(═O)cycloalkyl,
--C(═O)heterocyclyl, --C(═O)aryl, --C(═O)heteroaryl,
--C(═O)O-alkyl, --C(═O)O-cycloalkyl, --C(═O)O-heterocyclyl,
--C(═O)O-aryl, and --C(═O)O-heteroaryl; R1 is selected from
the group consisting of H and --C(R6)2-(Q)nR7; each
of R2, R3, R4, and R5 independently is H or alkyl;
each R6 independently is H or alkyl; R7 is selected from the
group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl,
--C(═O)N(R6)2, --C(═O)-alkyl, C(═O)-cycloalkyl,
C(═O)-heterocyclyl, --C(═O)-aryl, --C(═O)-heteroaryl,
--C(═O)--O-alkyl, --C(═O)--O-cycloalkyl,
--C(═O)--O-heterocyclyl, --C(═O)--O-aryl,
--C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R7 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; and Q is selected from the group
consisting of --NR6--, --O--, --S--, --S(O)--, and --S(O)2; and
n is 0 or 1.

14. The compound of claim 13, selected from the group consisting of:
##STR00160## or a pharmaceutically acceptable salt thereof.

15. A compound represented by Formula (VIII) ##STR00161## or a
pharmaceutically acceptable salt thereof; wherein: X is selected from the
group consisting of --S--, --O--, --S(O)2--, --S(O)--,
--(CR.sup.7.sub.2)p-- and --N(R')--; R' is selected from the group
consisting of H, alkyl, and aryl; T is heteroaryl, wherein said
heteroaryl is unsubstituted or substituted with a halo; Y is selected
from the group consisting of --OR6, --N(R6)2, and
--NR6--C(═O)N(R6)2; each of R1 and R2 is
independently H or alkyl; R3 is selected from the group consisting
of H or halo; each R6 independently is H or alkyl; each R7
independently is H, alkyl or aryl; and p is 1-3.

16. The compound of claim 15, selected from the group consisting of:
##STR00162## or a pharmaceutically acceptable salt thereof.

18. A compound selected from the group consisting of: ##STR00164##
##STR00165## ##STR00166## ##STR00167## or a pharmaceutically
acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of claim 1, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier.

20. (canceled)

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional
Application No. 61/099,732, filed Sep. 24, 2008, which is herein
incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates generally to novel hydantoin derivatives
that can inhibit matrix metalloproteinases (MMPs), a disintegrin and
metalloproteases (ADAMs) and/or tumor necrosis factor alpha-converting
enzyme (TACE) and in so doing prevent the release of tumor necrosis
factor alpha (TNF-α), pharmaceutical compositions comprising such
compounds, and methods of treatment using such compounds.

[0004] 2. Description

[0005] Osteo- and rheumatoid arthritis (OA and RA, respectively) are
destructive diseases of articular cartilage characterized by localized
erosion of the cartilage surface. Findings have shown that articular
cartilage from the femoral heads of patients with OA, for example, had a
reduced incorporation of radiolabeled sulfate over controls, suggesting
that there must be an enhanced rate of cartilage degradation in OA
(Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434). There are four
classes of protein degradative enzymes in mammalian cells: serine,
cysteine, aspartic and metalloproteases. The available evidence supports
the belief that it is the metalloproteases that are responsible for the
degradation of the extracellular matrix of articullar cartilage in OA and
RA. Increased activities of collagenases and stromelysin have been found
in OA cartilage and the activity correlates with severity of the lesion
Nankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al.
Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In
addition, aggrecanase (a newly identified metalloprotease) has been
identified that provides the specific cleavage product of proteoglycan,
found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36,
1993, 1214-22).

[0006] Metalloproteases (MPs) have been implicated as the key enzymes in
the destruction of mammalian cartilage and bone. It can be expected that
the pathogenesis of such diseases can be modified in a beneficial manner
by the administration of MP inhibitors (see Wahl et al. Ann. Rep. Med.
Chem. 25, 175-184, AP, San Diego, 1990).

[0007] MMPs are a family of over 20 different enzymes that are involved in
a variety of biological processes important in the uncontrolled breakdown
of connective tissue, including proteoglycan and collagen, leading to
resorption of the extracellular matrix. This is a feature of many
pathological conditions, such as RA and OA, corneal, epidermal or gastric
ulceration; tumor metastasis or invasion; periodontal disease and bone
disease. Normally these catabolic enzymes are tightly regulated at the
level of their synthesis as well as at their level of extracellular
activity through the action of specific inhibitors, such as
alpha-2-macroglobulins and TIMPs (tissue inhibitor of MPs), which form
inactive complexes with the MMP's.

[0009] TNF-α has been shown to play a pivotal role in immune and
inflammatory responses. Inappropriate or over-expression of TNF-α
is a hallmark of a number of diseases, including RA, Crohn's disease,
multiple sclerosis, psoriasis and sepsis. Inhibition of TNF-α
production has been shown to be beneficial in many preclinical models of
inflammatory disease, making inhibition of TNF-α production or
signaling an appealing target for the development of novel
anti-inflammatory drugs.

[0010] TNF-α is a primary mediator in humans and animals of
inflammation, fever and acute phase responses, similar to those observed
during acute infection and shock, Excess TNF-α has been shown to be
lethal. Blocking the effects of TNF-α with specific antibodies can
be beneficial in a variety of conditions, including autoimmune diseases
such as RA (Feldman et al, Lancet, (1994) 344, 1105), non-insulin
dependent diabetes mellitus (Lohmander L. S. et al., Arthritis Rheum. 36
(1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp.
Immunol. 81 (1990) 301).

[0011] Compounds that inhibit the production of TNF-α are therefore
of therapeutic importance for the treatment of inflammatory disorders.
Recently it has been shown that metalloproteases, such as TACE, are
capable of converting TNF-α from its inactive to active form
(Gearing et al Nature, 1994, 370, 555). Since excessive TNF-α
production has been noted in several disease conditions also
characterized by MMP-mediated tissue degradation, compounds which inhibit
both MMPs and TNF-α production may also have a particular advantage
in diseases where both mechanisms are involved.

[0012] One approach to inhibiting the harmful effects of TNF-α is to
inhibit the enzyme, TACE before it can process TNF-α to its soluble
form. TACE is a member of the ADAM family of type I membrane proteins and
mediates the ectodomain shedding of various membrane-anchored signaling
and adhesion proteins. TACE has become increasingly important in the
study of several diseases, including inflammatory disease, because of its
role in cleaving TNF-α from its "stalk" sequence and thus releasing
the soluble form of the TNF-α protein (Black R. A. Int J Biochem
Cell Biol. 2002 34, 1-5).

[0020] There is a need in the art for inhibitors of MMPs, ADAMs, TACE, and
TNF-α, which can be useful as anti-inflammatory compounds and
cartilage protecting therapeutics. The inhibition of TNF-α, TACE
and or other MMPs can prevent the degradation of cartilage by these
enzymes, thereby alleviating the pathological conditions of OA and RA as
well as many other auto-immune diseases.

SUMMARY OF THE INVENTION

[0021] In its many embodiments, the present invention provides a novel
class of compounds as inhibitors of TACE, the production of TNF-α,
MMPs, ADAMs, aggrecanase, or any combination thereof, methods of
preparing such compounds, pharmaceutical compositions comprising one or
more such compounds, methods of preparing pharmaceutical formulations
comprising one or more such compounds, and methods of treatment,
prevention, inhibition or amelioration of one or more diseases associated
with TACE, aggrecanaseTNF-α, MMPs, ADAMs or any combination thereof
using such compounds or pharmaceutical compositions.

[0022] In one embodiment, the present application discloses a compound
represented by Formula (I):

##STR00003##

or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0023] ring A is aryl or heteroaryl, wherein said aryl or heteroaryl is
unsubstituted or substituted with R2 or --OR3, wherein R2
is H or halo, and R3 is H or alkyl;

[0024] T is aryl or heteroaryl, substituted with an R4, R5, and
R6 as shown;

[0025] X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR82)p-- and --N(R')--;

[0026] p is 1 to 3;

[0027] R' is selected from the group consisting of H, alkyl, and aryl;

[0029] R1 is selected from the group consisting of H and
--C(R7)2-(Q)nR9;

[0030] R4 is selected from the group consisting of H, alkyl, and
halogen;

[0031] R5 and R6 are substituents on adjacent carbon atoms,
wherein R5 and R6 together with the carbon atoms to which they
are attached form a first five- to eight-membered cycloalkyl,
cycloalkenyl, heterocyclyl, or heterocyclenyl; wherein said first five-
to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or
heterocyclenyl contains two radicals on the same carbon atom, and said
radicals taken together with the carbon atom to which they are attached
form a second five- to eight-membered cycloalkyl, cycloalkenyl,
heterocyclyl, or heterocyclenyl; wherein said first five- to
eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl,
optionally with said second five- to eight-membered cycloalkyl,
cycloalkenyl, heterocyclyl, or heterocyclenyl is unsubstituted or
substituted with one to four R10 moieties;

[0032] each R7 independently is selected from the group consisting of
H, alkyl, and aryl;

[0033] each R8 independently is selected from the group consisting of
H, alkyl, and aryl;

[0034] R9 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R12)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring;

[0046] R1 is selected from the group consisting of H and
--C(R6)2-(Q)nR7;

[0047] R2 is selected from the group consisting of H, alkyl, and
halogen;

[0048] R3 and R4 are substituents on adjacent carbon atoms,
wherein R3 and R4 together with the carbon atoms to which they
are attached form a first five or six-membered heteroaryl, which is
unsubstituted or substituted with one or two substituents independently
selected from the group consisting of alkyl and cycloalkyl;

[0049] R5 is selected from the group consisting of alkyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl;

[0050] each R6 independently is selected from the group consisting of
H, alkyl, and aryl;

[0051] R7 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R8)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring;

[0052] each R8 is independently selected from the group consisting of
H and alkyl;

[0053] Q is selected from the group consisting of --NR8--, --O--,
--S--, --S(O)--, and --S(O)2--;

[0054] n is 0 or 1; and

[0055] m is 0-3.

[0056] In another embodiment, the present application discloses a compound
represented by Formula (III):

##STR00005##

or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0057] ring B is aryl or heteroaryl, wherein said aryl or heteroaryl is
unsubstituted or substituted with alkoxy;

[0058] at least one of T and V is present;

[0059] T is absent or present, and if present, is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0060] V is absent or present, and if present, is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0062] R1 is selected from the group consisting of H and
--C(R3)2-(Q)nR4;

[0063] each R3 independently is selected from the group consisting of
H, alkyl and aryl;

[0064] R4 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R5)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring;

[0065] Q is selected from the group consisting of --NR5--, --O--,
--S--, --S(O)--, and --S(O)2--;

[0066] each R5 is independently selected from the group consisting of
H and alkyl;

[0067] and n is 0 or 1.

[0068] In another embodiment, the present application discloses a compound
represented by Formula (IV):

##STR00006##

or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0069] ring A is aryl or heteroaryl, substituted on adjacent ring atoms
with R2, R3, and R4;

[0070] at least one of T and V is present;

[0071] T is absent or present, and if present, is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0072] V is absent or present, and if present, is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0073] X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR52)p-- and --N(R')--;

[0074] p is 1 to 3;

[0075] R' is selected from the group consisting of H, alkyl, and aryl;

[0077] R1 is selected from the group consisting of H and
--C(R6)2-(Q)nR7;

[0078] R2, R3, and R4 are substitutents on adjacent ring
atoms, wherein each of R2, R3, and R4 is independently
selected from the group consisting of halo, alkyl, and alkoxy;

[0079] each R5 independently is selected from the group consisting of
H, alkyl, and aryl;

[0080] each R6 independently is selected from the group consisting of
H, alkyl, and aryl;

[0081] R7 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R8)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryrl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring;

[0082] Q is selected from the group consisting of --NR8--, --O--,
--S--, and --S(O)2--;

[0083] each R8 is independently selected from the group consisting of
H and alkyl; and

[0084] n is 0 or 1.

[0085] In another embodiment, the present application discloses a compound
represented by Formula (V):

##STR00007##

or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0086] ring A is aryl or heteroaryl, wherein said aryl or heteroaryl is
unsubstituted or substituted with alkoxy or deuterium;

[0087] at least one of T and V is present, and at least one of T and V is
substituted with 1-3 R2 substituents;

[0088] T is absent or present, and if present is selected from the group
consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0089] V is absent or present, and if present is selected from the group
consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heterocyclenyl, and heteroaryl;

[0090] X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR72)p-- and --N(R')--;

[0091] p is 1 to 3;

[0092] R' is selected from the group consisting of H, alkyl, and aryl;

[0100] R9 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R6)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring.

[0101] In another embodiment, the present application discloses a compound
represented by Formula (VI):

##STR00008##

or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0102] ring A is aryl or heteroaryl, where said aryl or heteroaryl is
unsubstituted or is substituted with one or two substituents selected
from the group consisting of halo and alkoxy;

[0103] X is selected from the group consisting of --S--, --O--,
--S(O)2--, --S(O)--, --(CR72)p-- and --N(R')--;

[0104] p is 1 to 3;

[0105] Y is O or S;

[0106] T is aryl or heteroaryl;

[0107] R' is selected from the group consisting of H, alkyl, and aryl;

[0109] R1 is selected from the group consisting of H and
--C(R6)2-(Q)nR9;

[0110] Q is selected from the group consisting of --NR6--, --O--,
--S--, --S(O)--, and --S(O)2--;

[0111] n is 0 or 1;

[0112] each of R1 and R2 is independently H or alkyl;

[0113] each of R4 and R5 is independently selected from the
group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and
heteroaryl;

[0114] or wherein R4 and R5 together with the nitrogen atom to
which they are shown attached form a heterocyclyl or heteroaryl ring;

[0115] each R6 independently is H or alkyl;

[0116] each R7 independently is H, alkyl or aryl; and

[0117] R9 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R6)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R9 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring.

[0118] In another embodiment, the present application discloses a compound
represented by Formula (VII):

##STR00009##

or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0119] ring A is aryl, wherein said aryl is unsubstituted or substituted
with alkoxy;

[0120] T is heteroaryl, wherein when said T heteroaryl contains two
radicals on adjacent carbon atoms, said radicals may optionally be taken
together with the carbon atoms to which they are attached to form a five-
to eight membered heterocyclyl ring;

[0122] R1 is selected from the group consisting of H and
--C(R6)2-(Q)nR7;

[0123] each of R2, R3, R4, and R5 independently is H
or alkyl;

[0124] each R6 independently is H or alkyl;

[0125] R7 is selected from the group consisting of H, alkyl,
heterocyclyl, aryl, heteroaryl, --C(═O)N(R6)2,
--C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl,
--C(═O)-aryl, --C(═O)-heteroaryl, --C(═O)--O-alkyl,
--C(═O)--O-cycloalkyl, --C(═O)--O-heterocyclyl,
--C(═O)--O-aryl, --C(═O)--O-heteroaryl, --P(═O)(--OH)2,
--P(═O)(--O-alkyl)2, wherein when each of said "cycloalkyl",
"heterocyclyl", "aryl", or "heteroaryl" in any of the aforementioned
R7 groups contains two radicals on adjacent carbon atoms, said
radicals may optionally be taken together with the carbon atoms to which
they are attached to form a five- or six-membered cycloalkyl, aryl,
heterocyclyl or heteroaryl ring; and

[0126] Q is selected from the group consisting of --NR6--, --O--,
--S--, --S(O)--, and --S(O)2--; and

[0127] n is 0 or 1.

[0128] In another embodiment, the present application discloses a compound
represented by Formula (VIII):

##STR00010##

or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0129] X is selected from the group consisting of --S(O)2--,
--S(O)--, --(CR72)p-- and --N(R')--;

[0130] R' is selected from the group consisting of H, alkyl, and aryl;

[0131] T is heteroaryl, wherein said heteroaryl is unsubstituted or
substituted with a halo;

[0132] Y is selected from the group consisting of --OR6,
--N(R6)2, and --NR6--C(═O)N(R6)2;

[0133] each of R1 and R2 is independently H or alkyl;

[0134] R3 is selected from the group consisting of H or halo;

[0135] each R6 independently is H or alkyl;

[0136] each R7 independently is H, alkyl or aryl;

[0137] and p is 1-3.

[0138] In another embodiment, the present application discloses a compound
represented by Formula (IX):

##STR00011##

or a pharmaceutically acceptable salt or solvate thereof.

[0139] The compounds of Formulae (I)-(IX) can be useful as inhibitors of
TACE and may be useful in the treatment and prevention of diseases
associated with TACE, TNF-α, MMPs, ADAMs or any combination
thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0140] In its several embodiments, the present invention provides a novel
class of inhibitors of TACE, aggrecanase, the production of TNF-α,
MMPs, ADAMs or any combination thereof, pharmaceutical compositions
containing one or more of the compounds, methods of preparing
pharmaceutical formulations comprising one or more such compounds, and
methods of treatment, prevention or amelioration of one or more of the
symptoms of inflammation.

[0141] In one embodiment, the present invention provides compounds which
are represented by structural Formulae (I)-(IX) above or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof,
wherein the various moieties are as described above.

[0142] In another embodiment, in formula (I), said
T(R4)(R5)(R6) is

##STR00012##

[0143] In another embodiment, in formula (I), X is
--(CR82)p--.

[0144] In another embodiment, in formula (I), ring A is aryl or
heteroaryl.

[0145] In another embodiment, in formula (I), ring A is aryl or heteroaryl
substituted by --OR3 wherein R3 is H or alkyl.

[0146] In another embodiment, in formula (I), ring A is aryl or heteroaryl
substituted by --OCH3.

[0147] In another embodiment, in formula (I), ring A is aryl.

[0148] In another embodiment, in formula (I), ring A is phenyl.

[0149] In another embodiment, in formula (I), ring A is phenyl substituted
by --OR3 wherein R3 is H or alkyl.

[0150] In another embodiment, in formula (I), ring A is phenyl substituted
by --OCH3.

[0151] In another embodiment, in formula (I), X is
--(CR82)p--, wherein R8 is H.

[0152] In another embodiment, in formula (I), X is
--(CR82)p--, wherein p is 1 or 2.

[0153] In another embodiment, in formula (I), R is H.

[0154] In another embodiment, in formula (I), R1 is H.

[0155] In another embodiment, in formula (I), R4 is H.

[0156] In another embodiment, in formula (I), R5 and R6 together
with the carbon atoms to which they are attached form a five- or
six-membered cycloalkyl, wherein said five- or six-membered cycloalkyl
contains two radicals on the same carbon atom, said radicals taken
together with the carbon atom to which they are attached form a
five-membered heterocyclyl.

[0157] In another embodiment, in formula (I), R5 and R6 together
with the carbon atoms to which they are attached form a five- or
six-membered cycloalkyl, wherein said five- or six-membered cycloalkyl
contains two radicals on the same carbon atom, said radicals taken
together with the carbon atom to which they are attached form a
five-membered heterocyclyl, wherein said five- or six-membered cycloalkyl
comprising R5 and R6 and further comprising said five-membered
heterocyclyl is selected from the group consisting of:

##STR00013##

each of which is unsubstituted or independently substituted with one to
four R10 moieties.

[0158] In another embodiment, formula (I), formula (I) is selected from
the group consisting of Formula (IA)

##STR00014##

and Formula (IB):

##STR00015##

[0159] wherein in each of Formula (IA) and (IB), R2 is selected from
the group consisting of H, alkyl, and halo; and R3 is selected from
the group consisting of H and alkyl.

[0160] In another embodiment, in formula (IA) or (IB), R2 is selected
from the group consisting of H and halo.

[0161] In another embodiment, in formula (IA) or (IB), R2 is selected
from the group consisting of H and fluoro.

[0162] In another embodiment, the compound of formula (I) is selected from
the group consisting of:

##STR00016## ##STR00017##

or a pharmaceutically acceptable salt or solvate thereof.

[0163] In another embodiment, in formula (II), T is heteroaryl and is
represented by

##STR00018##

wherein:

[0164] ring A is pyridine substituted with m R5 substituents on
carbon atoms as shown.

[0165] In another embodiment, in formula (II), X is
--(CR62)p--.

[0166] In another embodiment, in formula (II), X is
--(CR62)p--, wherein R8 is H.

[0167] In another embodiment, in formula (II), X is
--(CR62)p--, wherein p is 1 or 2.

[0168] In another embodiment, in formula (II), X is
--(CR62)p--, wherein p is 1.

[0169] In another embodiment, in formula (II), R is H.

[0170] In another embodiment, in formula (II), R1 is H.

[0171] In another embodiment, in formula (II), R2 is selected from
the group consisting of H and halo.

[0172] In another embodiment, in formula (II), R2 is selected from
the group consisting of H and fluoro.

[0173] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a first
five or six-membered heteroaryl, which is unsubstituted or substituted
with a substituent selected from the group consisting of alkyl,
alkoxyalkyl, benzyl, and cycloalkyl.

[0174] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a furanyl
group which is unsubstituted or substituted with a substituent selected
from the group consisting of alkyl and cycloalkyl.

[0175] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a furanyl
group which is unsubstituted or substituted with a substituent selected
from the group consisting of alkyl, alkoxyalkyl, benzyl, and cycloalkyl.

[0176] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a furanyl
group which is unsubstituted or substituted with a substituent selected
from the group consisting of alkyl and cycloalkyl, wherein said alkyl
substituent is unsubstituted or substituted with an alkoxy or an aryl
group.

[0177] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a furanyl
group which is unsubstituted or substituted with a substituent selected
from the group consisting of alkyl and cycloalkyl, wherein said alkyl
substituent is selected from the group consisting of methyl,
methoxymethyl, and benzyl.

[0178] In another embodiment, in formula (II), R3 and R4
together with the carbon atoms to which they are attached form a furanyl
group which is unsubstituted or substituted with a substituent selected
from the group consisting of alkyl and cycloalkyl, wherein said
cycloalkyl is cyclopropyl.

[0179] In another embodiment, in formula (II), m is 0.

[0180] In another embodiment, in formula (II), m is 1.

[0181] In another embodiment, in formula (II), R5 is heteroaryl.

[0182] In another embodiment, in formula (II), R5 is pyrazolyl.

[0183] In another embodiment, the compound of formula (II) is elected from
the group consisting of:

##STR00019##

or a pharmaceutically acceptable salt or solvate thereof.

[0184] In another embodiment, in formula (III), ring B is aryl or
heteroaryl.

[0185] In another embodiment, in formula (III), ring B is aryl or
heteroaryl substituted with an alkoxy.

[0186] In another embodiment, in formula (III), ring B is aryl.

[0187] In another embodiment, in formula (III), ring B is phenyl.

[0188] In another embodiment, in formula (III), said ring B phenyl is
substituted with an alkoxy.

[0189] In another embodiment, in formula (III), said ring B phenyl is
substituted with an alkoxy, wherein said alkoxy is methoxy.

[0190] In another embodiment, in formula (III), T alkynyl is
--C≡C--.

[0191] In another embodiment, in formula (III), V heteroaryl is pyridyl.

[0192] In another embodiment, in formula (III), R is H.

[0193] In another embodiment, in formula (III), R1 is H.

[0194] In another embodiment, the compound of formula (III) is selected
from the group consisting of:

##STR00020##

or a pharmaceutically acceptable salt or solvate thereof.

[0195] In another embodiment, in formula (IV), ring A is aryl.

[0196] In another embodiment, in formula (IV), T is selected from the
group consisting of alkynyl and heteroaryl.

[0197] In another embodiment, in formula (IV), V is aryl or heteroaryl.

[0198] In another embodiment, the compound of formula (IV) is represented
by formula (IVA):

[0200] T is selected from the group consisting of alkynyl and heteroaryl;
and

[0201] V is absent or present, and if present, is selected from the group
consisting of aryl and heterocyclyl.

[0202] In another embodiment, in formula (IV), said T alkynyl is
--C≡C--.

[0203] In another embodiment, in formula (IV), said T heteroaryl is

##STR00022##

wherein ring B is pyridine.

[0204] In another embodiment, in formula (IV), said V heterocyclyl is
selected from the group consisting of piperidinyl, and

##STR00023##

each of which independently is unsubstituted or substituted with one or
two substituents independently selected from the group consisting of
--NH2, --NH(alkyl), --N(alkyl)2, and aminoalkyl.

[0205] In another embodiment, in formula (IV), said V aryl is phenyl which
is unsubstituted or substituted with one to two substitutents selected
from the group consisting of --C(═O)NH2, --C(═O)NH(alkyl),
and --C(═O)N(alkyl)2.

[0206] In another embodiment, in formula (IV), R is H.

[0207] In another embodiment, in formula (IV), R1 is H.

[0208] In another embodiment, in formula (IV), R2 is halo.

[0209] In another embodiment, in formula (IV), R2 is fluoro or
chloro.

[0210] In another embodiment, in formula (IV), R3 is alkoxy.

[0211] In another embodiment, in formula (IV), R3 is methoxy.

[0212] In another embodiment, in formula (IV), R4 is halo.

[0213] In another embodiment, in formula (IV), R4 is fluoro or
chloro.

[0214] In another embodiment, in formula (IV), X is
--(CR52)p--.

[0215] In another embodiment, in formula (IV), X is
--(CR52)p--, wherein R5 is H.

[0216] In another embodiment, in formula (IV), X is
--(CR52)p--, wherein p is 1.

[0217] In another embodiment, the compound of formula (IV) is selected
from the group consisting of:

##STR00024## ##STR00025##

or a pharmaceutically acceptable salt or solvate thereof.

[0218] In another embodiment, in formula (V),

[0219] at least one of T and V is substituted with an R2 substituent;
and

[0220] at least one of T and V is present, and at least one of T and V is
substituted with an R2 substituent.

[0221] In another embodiment, in formula (V):

[0222] ring A is aryl;

[0223] only one of T and V is present and is heteroaryl which is
substituted with an R2.

[0224] In another embodiment, in formula (V):

[0225] ring A is aryl;

[0226] both T and V are present;

[0227] T is --C≡C--; and

[0228] V is selected from the group consisting of aryl and heteroaryl,
each of which is substituted with R2.

[0229] In another embodiment, in formula (V), at least one of T and V is
substituted with an R2 substituent.

[0230] In another embodiment, in formula (V), ring A is aryl or
heteroaryl.

[0231] In another embodiment, in formula (V), ring A is aryl or heteroaryl
substituted with an alkoxy.

[0232] In another embodiment, in formula (V), ring A is phenyl substituted
with an alkoxy.

[0233] In another embodiment, in formula (V), ring A is phenyl substituted
with a methoxy.

[0234] In another embodiment, in formula (V), said V aryl is phenyl.

[0235] In another embodiment, in formula (V), said V heteroaryl is
thiophenyl.

[0236] In another embodiment, in formula (V), X is
--(CR72)p--.

[0237] In another embodiment, in formula (V), X is
--(CR72)p--, wherein R7 is H.

[0238] In another embodiment, in formula (V), X is
--(CR72)p--, wherein p is 1.

[0239] In another embodiment, in formula (V), wherein R' is H.

[0240] In another embodiment, in formula (V), wherein R is H.

[0241] In another embodiment, in formula (V), wherein R1 is H.

[0242] In another embodiment, in formula (V), R3 is selected from the
group consisting of: --C(═N--OH)--N(alkyl)2,
--C(═O)NHS(═O)2NH2,
--C(H)((C═O)OH)-heterocyclyl-C(═O)Oalkyl,
--C(H)((C═O)(H2)-heterocyclyl-C(═O)Oalkyl,
--NH--C(═S)N(H)-alkyl-heterocyclyl, --C(═NH)NHOH,
--C(═NH)-heterocyclyl-alkyl, and --C(═NH)--NH2.

[0243] In another embodiment, the compound of formula (V) is selected from
the group consisting of:

##STR00026## ##STR00027## ##STR00028## ##STR00029##

or a pharmaceutically acceptable salt or solvate thereof.

[0244] In another embodiment, in formula (VI), X is
--(CR72)p--.

[0245] In another embodiment, in formula (VI), X is
--(CR72)p--, wherein R7 is H.

[0246] In another embodiment, in formula (VI), X is
--(CR72)p--, wherein p is 1.

[0247] In another embodiment, in formula (VI), R' is H.

[0248] In another embodiment, in formula (VI), R is H.

[0249] In another embodiment, in formula (VI), R1 is H.

[0250] In another embodiment, in formula (VI), ring A is aryl or
heteroaryl.

[0251] In another embodiment, in formula (VI), ring A is aryl or
heteroaryl, which is substituted with one or two substituents selected
from the group consisting of halo and alkoxy.

[0252] In another embodiment, in formula (VI), ring A is aryl.

[0253] In another embodiment, in formula (VI), ring A is phenyl.

[0254] In another embodiment, in formula (VI), ring A is phenyl, which is
substituted with one or two substituents selected from the group
consisting of halo and alkoxy.

[0255] In another embodiment, in formula (VI), ring A is phenyl, which is
substituted with one or two substituents selected from the group
consisting of fluoro and methoxy.

[0256] In another embodiment, in formula (VI), Y is O.

[0257] In another embodiment, in formula (VI), T is heteroaryl wherein
said heteroaryl is pyridyl.

[0258] In another embodiment, in formula (VI). T is pyridyl which is
substituted with a hydroxy substituent.

[0259] In another embodiment, in formula (VI), --NR4R5 is
selected from the group consisting of --NH(heteroaryl),
--NH(heterocyclyl) and heterocyclyl.

[0260] In another embodiment, the compound of formula (VI) is selected
from the group consisting of:

##STR00030##

or a pharmaceutically acceptable salt or solvate thereof.

[0261] In another embodiment, in formula (VII), ring A is aryl which is
unsubstituted or is substituted with an alkoxy.

[0262] In another embodiment, in formula (VII), ring A is aryl which is
substituted with an alkoxy.

[0263] In another embodiment, in formula (VII), ring A is aryl.

[0264] In another embodiment, in formula (VII), ring A is phenyl.

[0265] In another embodiment, in formula (VII), ring A is phenyl, which is
unsubstituted or substituted with an alkoxy.

[0266] In another embodiment, in formula (VII), ring A is phenyl, which is
unsubstituted or substituted with a methoxy.

[0267] In another embodiment, in formula (VII), said T heteroaryl,
optionally with said five- to eight membered heterocyclyl ring is
selected from the group consisting of:

##STR00031##

wherein ring B is pyridyl and R8 is H or alkyl.

[0268] In another embodiment, in formula (VII), when said T heteroaryl,
optionally with said five- to eight membered heterocyclyl ring is

##STR00032##

ring B pyridyl is unsubstituted or substituted with a heteroaryl.

[0269] In another embodiment, in formula (VII), when said T heteroaryl,
optionally with said five- to eight membered heterocyclyl ring is

##STR00033##

ring B pyridyl is substituted with a pyrazolyl.

[0270] In another embodiment, in formula (VII), R is H.

[0271] In another embodiment, in formula (VII), R1 is H.

[0272] In another embodiment, in formula (VII), R2, R3, R4,
and R5 are all H.

[0273] In another embodiment, the compound of formula (VII) is selected
from the group consisting of:

##STR00034##

or a pharmaceutically acceptable salt or solvate thereof.

[0274] In another embodiment, in formula (VIII), X is
--(CR72)p--.

[0275] In another embodiment, in formula (VIII), X is
--(CR72)p--, wherein R7 is H.

[0276] In another embodiment, in formula (VIII), X is
--(CR72)p--, wherein p is 1.

[0277] In another embodiment, in formula (VIII), T is heteroaryl.

[0278] In another embodiment, in formula (VIII), T is

##STR00035##

wherein ring A is pyridyl.

[0279] In another embodiment, in formula (VIII), T is

##STR00036##

wherein ring A is pyridyl, wherein said pyridyl is substituted with a
halo.

[0280] In another embodiment, in formula (VIII), Y is selected from the
group consisting of --NH2, --OH, and --NHC(═O)NH2.

[0281] In another embodiment, in formula (VIII), R2 is alkyl.

[0282] In another embodiment, in formula (VIII), R2 is methyl.

[0283] In another embodiment, in formula (VIII), R3 is selected from
the group consisting of H and fluoro.

[0284] In another embodiment, the compound of formula (VIII) is selected
from the group consisting of:

##STR00037##

or a pharmaceutically acceptable salt or solvate thereof.

[0285] In another embodiment, the present invention provides a compound
selected from the group consisting of:

##STR00038## ##STR00039## ##STR00040## ##STR00041##

or a pharmaceutically acceptable salt or solvate thereof.

[0286] As used above, and throughout this disclosure, the following terms,
unless otherwise indicated, shall be understood to have the following
meanings:

[0287] "Patient" includes both human and animals.

[0288] "Mammal" means humans and other mammalian animals.

[0289] "Alkyl" means an aliphatic hydrocarbon group which may be straight
or branched and comprising about 1 to about 20 carbon atoms in the chain.
Preferred alkyl groups contain about 1 to about 12 carbon atoms in the
chain. More preferred alkyl groups contain about 1 to about 6 carbon
atoms in the chain. Branched means that one or more lower alkyl groups
such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
"Lower alkyl" means a group having about 1 to about 6 carbon atoms in the
chain which may be straight or branched. The alkyl group may be
substituted by one or more substituents which may be the same or
different, each substituent being independently selected from the group
consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, cyano, hydroxy,
alkoxy, alkylthio, amino, oxime (e.g., ═N--OH), --NH(alkyl),
--NH(cycloalkyl), --N(alkyl)2, --O--C(O)-alkyl, --O--C(O)-aryl,
--O--C(O)-cycloalkyl, carboxy and --C(O)O-alkyl. Non-limiting examples of
suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and
t-butyl.

[0290] "Alkenyl" means an aliphatic hydrocarbon group containing at least
one carbon-carbon double bond and which may be straight or branched and
comprising about 2 to about 15 carbon atoms in the chain. Preferred
alkenyl groups have about 2 to about 12 carbon atoms in the chain; and
more preferably about 2 to about 6 carbon atoms in the chain. Branched
means that one or more lower alkyl groups such as methyl, ethyl or
propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means
about 2 to about 6 carbon atoms in the chain which may be straight or
branched. "Alkenyl" may be unsubstituted or optionally substituted by one
or more substituents which may be the same or different, each substituent
being independently selected from the group consisting of halo, alkyl.
aryl, heteroaryl, cycloalkyl, cyano, alkoxy and --S(alkyl). Non-limiting
examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl,
3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

[0291] "Alkylene" means a difunctional group obtained by removal of a
hydrogen atom from an alkyl group that is defined above. Non-limiting
examples of alkylene include methylene, ethylene and propylene.

[0292] "Alkynyl" means an aliphatic hydrocarbon group containing at least
one carbon-carbon triple bond and which may be straight or branched and
comprising about 2 to about 15 carbon atoms in the chain. Preferred
alkynyl groups have about 2 to about 12 carbon atoms in the chain; and
more preferably about 2 to about 4 carbon atoms in the chain. Branched
means that one or more lower alkyl groups such as methyl, ethyl or
propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means
about 2 to about 6 carbon atoms in the chain which may be straight or
branched. Non-limiting examples of suitable alkynyl groups include
ethynyl, propynyl, 2-butyryl and 3-methylbutynyl. "Alkynyl" may be
unsubstituted or optionally substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of alkyl, aryl and cycloalkyl.

[0293] "Aryl" means an aromatic monocyclic or multicyclic ring system
comprising about 6 to about 14 carbon atoms, preferably about 6 to about
10 carbon atoms. The aryl group can be optionally substituted with one or
more "ring system substituents" which may be the same or different, and
are as defined herein. Non-limiting examples of suitable aryl groups
include phenyl and naphthyl.

[0294] "Heteroaryl" means an aromatic monocyclic or multicyclic ring
system comprising about 5 to about 14 ring atoms, preferably about 5 to
about 10 ring atoms, in which one or more of the ring atoms is an element
other than carbon, for example nitrogen, oxygen or sulfur, alone or in
combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
The "heteroaryl" can be optionally substituted by one or more "ring
system substituents" which may be the same or different, and are as
defined herein. The prefix aza, oxa or thia before the heteroaryl root
name means that at least a nitrogen, oxygen or sulfur atom respectively,
is present as a ring atom. A nitrogen atom of a heteroaryl can be
optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also
include a heteroaryl as defined above fused to an aryl as defined above.
Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl,
furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted
pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,
furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,
pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,
indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,
imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl,
imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl,
benzothiazolyl and the like. The term "heteroaryl" also refers to
partially saturated heteroaryl moieties such as, for example,
tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

[0295] "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the
aryl and alkyl are as previously described. Preferred aralkyls comprise a
lower alkyl group. Non-limiting examples of suitable aralkyl groups
include benzyl. 2-phenethyl and naphthalenylmethyl. The bond to the
parent moiety is through the alkyl.

[0296] "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl
are as previously described. Preferred alkylaryls comprise a lower alkyl
group. Non-limiting example of a suitable alkylaryl group is tolyl. The
bond to the parent moiety is through the aryl.

[0297] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system
comprising about 3 to about 10 carbon atoms, preferably about 5 to about
10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7
ring atoms. The cycloalkyl can be optionally substituted with one or more
"ring system substituents" which may be the same or different, and are as
defined above. Non-limiting examples of suitable monocyclic cycloalkyls
include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like.

[0299] "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system
comprising about 3 to about 10 carbon atoms, preferably about 5 to about
10 carbon atoms which contains at least one carbon-carbon double bond.
Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The
cycloalkenyl can be optionally substituted with one or more "ring system
substituents" which may be the same or different, and are as defined
above. Non-limiting examples of suitable monocyclic cycloalkenyls include
cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.
Non-limiting example of a suitable multicyclic cycloalkenyl is
norbornylenyl.

[0302] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces an
available hydrogen on the ring system. Ring system substituents may be
the same or different, each being independently selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,
alkylaryl, heteroaralkyl, heteroarylalkenyi, heteroarylalkynyl,
alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,
aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,
cycloalkyl, heterocyclyl, --O--C(O)-alkyl, --O--C(O)-aryl,
--O--C(O)-cycloalkyl, --C(═N--CN)--NH2, --C(═NH)--NH2,
--C(═NH)--NH(alkyl), oxime (e.g., ═N--OH), --NY1Y2,
-alkyl-NY1Y2, --C(O)NY1Y2, --SO2NY1Y2
and --SO2NY1Y2, wherein Y1 and Y2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring
system substituent" may also mean a single moiety which simultaneously
replaces two available hydrogens on two adjacent carbon atoms (one H on
each carbon) on a ring system. Examples of such moiety are methylene
dioxy, ethylenedioxy, --C(CH3)2-- and the like which form
moieties such as, for example:

##STR00042##

[0303] "Heteroarylalkyl" means a heteroaryl moiety as defined above linked
via an alkyl moiety (defined above) to a parent core. Non-limiting
examples of suitable heteroaryls include 2-pyridinylmethyl,
quinolinylmethyl and the like. "Heterocyclyl" means a non-aromatic
saturated monocyclic or multicyclic ring system comprising about 3 to
about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which
one or more of the atoms in the ring system is an element other than
carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
There are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain about 5 to about 6 ring atoms.
The prefix aza, oxa or thia before the heterocyclyl root name means that
at least a nitrogen, oxygen or sulfur atom respectively is present as a
ring atom. Any --NH in a heterocyclyl ring may exist protected such as,
for example, as an --N(Boc), --N(CBz), --N(Tos) group and the like; such
protections are also considered part of this invention. The heterocyclyl
can be optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples
of suitable monocyclic heterocyclyl rings include piperidyl,
pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,
1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone,
and the like. "Heterocyclyl" also includes heterocyclyl rings as
described above wherein ═O replaces two available hydrogens on the
same ring carbon atom. Example of such moiety is pyrrolidone:

[0305] "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic
ring system comprising about 3 to about 10 ring atoms, preferably about 5
to about 10 ring atoms, in which one or more of the atoms in the ring
system is an element other than carbon, for example nitrogen, oxygen or
sulfur atom, alone or in combination, and which contains at least one
carbon-carbon double bond or carbon-nitrogen double bond. There are no
adjacent oxygen and/or sulfur atoms present in the ring system. Preferred
heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix
aza, oxa or thia before the heterocyclenyl root name means that at least
a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
The heterocyclenyl can be optionally substituted by one or more ring
system substituents, wherein "ring system substituent" is as defined
above. The nitrogen or sulfur atom of the heterocyclenyl can be
optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable heterocyclenyl groups include
1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,
1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl,
3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl,
dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl,
3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl,
7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and
the like. "Heterocyclenyl" also includes heterocyclenyl rings as
described above wherein ═O replaces two available hydrogens on the
same ring carbon atom. Example of such moiety is pyrrolidinone:

[0307] It should be noted that in hetero-atom containing ring systems of
this invention, there are no hydroxyl groups on carbon atoms adjacent to
a N, O or S, as well as there are no N or S groups on carbon adjacent to
another heteroatom. Thus, for example, in the ring:

##STR00045##

there is no --OH attached directly to carbons marked 2 and 5.

[0308] It should also be noted that tautomeric forms such as, for example,
the moieties:

##STR00046##

are considered equivalent in certain embodiments of this invention.

[0309] "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl
and alkyl are as previously described. Preferred alkynylalkyls contain a
lower alkynyl and a lower alkyl group. The bond to the parent moiety is
through the alkyl. Non-limiting examples of suitable alkynylalkyl groups
include propargylmethyl.

[0310] "Heteroaralkyl" means a heteroaryl-alkyl- group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples of
suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl.
The bond to the parent moiety is through the alkyl.

[0311] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.

[0312] "Acyl" means an H--C(O)--, alkyl-C(O)-- or cycloalkyl-C(O)--, group
in which the various groups are as previously described. The bond to the
parent moiety is through the carbonyl. Preferred acyls contain a lower
alkyl. Non-limiting examples of suitable acyl groups include formyl,
acetyl and propanoyl.

[0313] "Aroyl" means an aryl-C(O)-- group in which the aryl group is as
previously described. The bond to the parent moiety is through the
carbonyl. Non-limiting examples of suitable groups include benzoyl and
1-naphthoyl.

[0314] "Alkoxy" means an alkyl-O-- group in which the alkyl group is as
previously described. Non-limiting examples of suitable alkoxy groups
include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to
the parent moiety is through the ether oxygen.

[0315] "Aryloxy" means an aryl-O-- group in which the aryl group is as
previously described. Non-limiting examples of suitable aryloxy groups
include phenoxy and naphthoxy. The bond to the parent moiety is through
the ether oxygen.

[0316] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl group
is as previously described. Non-limiting examples of suitable aralkyloxy
groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the
parent moiety is through the ether oxygen.

[0317] "Alkylthio" means an alkyl-S-- group in which the alkyl group is as
previously described. Non-limiting examples of suitable alkylthio groups
include methylthio and ethylthio. The bond to the parent moiety is
through the sulfur.

[0318] "Arylthio" means an aryl-S-- group in which the aryl group is as
previously described. Non-limiting examples of suitable arylthio groups
include phenylthio and naphthylthio. The bond to the parent moiety is
through the sulfur.

[0319] "Aralkylthio" means an aralkyl-S-- group in which the aralkyl group
is as previously described. Non-limiting example of a suitable
aralkylthio group is benzylthio. The bond to the parent moiety is through
the sulfur.

[0320] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl and
ethoxycarbanyl. The bond to the parent moiety is through the carbonyl.

[0321] "Aryloxycarbonyl" means an aryl-O--C(O)-- group. Non-limiting
examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and
naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0322] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group. Non-limiting
example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The
bond to the parent moiety is through the carbonyl.

[0323] "Alkylsulfonyl" means an alkyl-S(O2)-- group. Preferred groups
are those in which the alkyl group is lower alkyl. The bond to the parent
moiety is through the sulfonyl.

[0324] "Arylsulfonyl" means an aryl-S(O2)-- group. The bond to the
parent moiety is through the sulfonyl.

[0325] The term "substituted" means that one or more hydrogens on the
designated atom is replaced with a selection from the indicated group,
provided that the designated atom's normal valency under the existing
circumstances is not exceeded, and that the substitution results in a
stable compound. Combinations of substituents and/or variables are
permissible only if such combinations result in stable compounds. By
"stable compound" or "stable structure" is meant a compound that is
sufficiently robust to survive isolation to a useful degree of purity
from a reaction mixture, and formulation into an efficacious therapeutic
agent.

[0326] The term "optionally substituted" means optional substitution with
the specified groups, radicals or moieties.

[0327] The term "purified", "in purified form" or "in isolated and
purified form" for a compound refers to the physical state of said
compound after being isolated from a synthetic process (e.g. from a
reaction mixture), or natural source or combination thereof. Thus, the
term "purified", "in purified form" or "in isolated and purified form"
for a compound refers to the physical state of said compound after being
obtained from a purification process or processes described herein or
well known to the skilled artisan (e.g., chromatography,
recrystallization and the like), in sufficient purity to be
characterizable by standard analytical techniques described herein or
well known to the skilled artisan.

[0328] It should also be noted that any carbon as well as heteroatom with
unsatisfied valences in the text, schemes, examples and Tables herein is
assumed to have the sufficient number of hydrogen atom(s) to satisfy the
valences.

[0329] When a functional group in a compound is termed "protected", this
means that the group is in modified form to preclude undesired side
reactions at the protected site when the compound is subjected to a
reaction. Suitable protecting groups will be recognized by those with
ordinary skill in the art as well as by reference to standard textbooks
such as, for example, T. W. Greene et al, Protective Groups in organic
Synthesis (1991), Wiley, New York.

[0330] When any variable (e.g., aryl, heterocycle, R2, etc.) occurs
more than one time in any constituent or in Formulae (I)-(IX), its
definition on each occurrence is independent of its definition at every
other occurrence.

[0331] As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as
well as any product which results, directly or indirectly, from
combination of the specified ingredients in the specified amounts.

[0332] Prodrugs and solvates of the compounds of the invention are also
contemplated herein. The term "prodrug", as employed herein, denotes a
compound that is a drug precursor which, upon administration to a
subject, undergoes chemical conversion by metabolic or chemical processes
to yield a compound of Formulae (I)-(IX) or a salt and/or solvate
thereof. A discussion of prodrugs is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)
Edward B. Roche, ed., American Pharmaceutical Association and Pergamon
Press, both of which are incorporated herein by reference thereto. The
term "prodrug" means a compound (e.g, a drug precursor) that is
transformed in vivo to yield a compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms (e.g., by metabolic or
chemical processes), such as, for example, through hydrolysis in blood. A
discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press,
1987.

[0333] For example, if a compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, hydrate or solvate of the compound
contains a carboxylic acid functional group, a prodrug can comprise an
ester formed by the replacement of the hydrogen atom of the acid group
with a group such as, for example, (C1-C8)alkyl,
(C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4
to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10
carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,
N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,
3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C1-C2)alkylamino(C2-C3)alkyl (such as
β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di
(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-,
pyrrolidino- or morpholino(C2-C3)alkyl, and the like.

[0334] Similarly, if a compound of Formula (I)-(IX) contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as, for example,
(C1-C6)alkanoyloxymethyl,
1-((C1-C6)alkanoyloxy)ethyl,
1-methyl-1-((C1-C6)alkanoyloxy)ethyl,
(C1-C6)alkoxycarbonyloxymethyl,
N--(C1-C6)alkoxycarbonylaminomethyl, succinoyl,
(C1-C6)alkanoyl, α-amino(C1-C4)alkanyl,
arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl,
where each α-aminoacyl group is independently selected from the
naturally occurring L-amino acids. P(O)(OH)2,
--P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting
from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate), and the like.

[0335] If a compound of Formulae (I)-(IX) incorporates an amine functional
group, a prodrug can be formed by the replacement of a hydrogen atom in
the amine group with a group such as, for example, R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or
R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl,
--C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or
benzyl, --C(OY2)Y3 wherein Y2 is (C1-C4)alkyl
and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl,
amino(C1-C4)alkyl or mono-N-- or
di-N,N--(C1-C6)alkylaminoalkyl, --C(Y4)Y5 wherein
Y4 is H or methyl and Y5 is mono-N-- or
di-N,N--(C1-C6)alkylamino morpholino, piperidin-1-yl or
pyrrolidin-1-yl, and the like.

[0336] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical association
involves varying degrees of ionic and covalent bonding, including
hydrogen bonding. In certain instances the solvate will be capable of
isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid. "Solvate"
encompasses both solution-phase and isolatable solvates. Non-limiting
examples of suitable solvates include ethanolates, methanolates, and the
like. "Hydrate" is a solvate wherein the solvent molecule is H2O.

[0337] "Effective amount" or "therapeutically effective amount" is meant
to describe an amount of compound or a composition of the present
invention effective in inhibiting TACE, the production of TNF-α,
MMPs, ADAMS or any combination thereof and thus producing the desired
therapeutic, ameliorative, inhibitory or preventative effect.

[0338] The compounds of Formulae (I)-(IX) can form salts which are also
within the scope of this invention. Reference to a compound of Formulae
(I)-(IX) herein is understood to include reference to salts thereof,
unless otherwise indicated. The term "salt(s)", as employed herein,
denotes acidic salts formed with inorganic and/or organic acids, as well
as basic salts formed with inorganic and/or organic bases. In addition,
when a compound of Formulae (I)-(IX) contains both a basic moiety, such
as, but not limited to a pyridine or imidazole, and an acidic moiety,
such as, but not limited to a carboxylic acid, zwitterions ("inner
salts") may be formed and are included within the term "salt(s)" as used
herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable) salts are preferred, although other salts are also useful.
Salts of the compounds of the Formulae (I)-(IX) may be formed, for
example, by reacting a compound of Formulae (I)-(IX) with an amount of
acid or base, such as an equivalent amount, in a medium such as one in
which the salt precipitates or in an aqueous medium followed by
lyophilization.

[0341] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention and
all acid and base salts are considered equivalent to the free forms of
the corresponding compounds for purposes of the invention.

[0342] Compounds of Formulae (I)-(IX), and salts, solvates and prodrugs
thereof, may exist in their tautomeric form (for example, as an amide or
imino ether). All such tautomeric forms are contemplated herein as part
of the present invention.

[0343] All stereoisomers (for example, geometric isomers, optical isomers
and the like) of the present compounds (including those of the salts,
solvates and prodrugs of the compounds as well as the salts and solvates
of the prodrugs), such as those which may exist due to asymmetric carbons
on various substituents, including enantiomeric forms (which may exist
even in the absence of asymmetric carbons), rotameric forms,
atropisomers, and diastereomeric forms, are contemplated within the scope
of this invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of
the invention may, for example, be substantially free of other isomers,
or may be admixed, for example, as racemates or with all other, or other
selected, stereoisomers. The chiral centers of the present invention can
have the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate" "prodrug" and the
like, is intended to equally apply to the salt, solvate and prodrug of
enantiomers, stereoisomers, rotamers, tautomers, positional isomers,
racemates or prodrugs of the inventive compounds.

[0344] The present invention also embraces isotopically-labelled compounds
of the present invention which are identical to those recited herein, but
for the fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be incorporated
into compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as
2H, 3H, 11C, 13C, 14C.sub., 15N, 18O,
17O, 31P, 32P, 35S, 18F, 36Cl and
123I, respectively.

[0345] Certain isotopically-labelled compounds of Formulae (I)-(IX) (e.g.,
those labeled with 3H and 14C) are useful in compound and/or
substrate tissue distribution assays. Tritiated (i.e., 3H) and
carbon-14 (i.e., 14C) isotopes are particularly preferred for their
ease of preparation and detectability. Certain isotopically-labelled
compounds of Formula (I) can be useful for medical imaging purposes such
as those labeled with positron-emitting isotopes like 11C or
18F can be useful for application in Positron Emission Tomography
(PET) and those labeled with gamma ray emitting isotopes like 123I
can be useful for application in Single photon emission computed
tomography (SPECT). Further, substitution with heavier isotopes such as
deuterium (i.e., 2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be preferred in
some circumstances. Additionally, isotopic substitution at a site where
epimerization occurs may slow or reduce the epimerization process and
thereby retain the more active or efficacious form of the compound for a
longer period of time. Isotopically labeled compounds of Formula (I), in
particular those containing isotopes with longer half lives (T1/2>1
day), can generally be prepared by following procedures analogous to
those disclosed in the Schemes and/or in the Examples herein below, by
substituting an appropriate isotopically labeled reagent for a
non-isotopically labeled reagent.

[0346] Polymorphic forms of the compounds of Formulae (I)-(IX), and of the
salts, solvates and prodrugs of the compounds of Formulae (I)-(IX) are
intended to be included in the present invention.

[0347] The compounds according to the invention have pharmacological
properties; in particular, the compounds of Formulae (I)-(IX) can be
inhibitors of TACE, aggrecanase, TNF-α and/or MMP activity.

[0348] In one aspect, the invention provides a pharmaceutical composition
comprising as an active ingredient at least one compound of Formulae
(I)-(IX).

[0349] In another aspect, the invention provides a pharmaceutical
composition comprising at least one compound of Formulae (I)-(IX) and
additionally comprising at least one pharmaceutically acceptable carrier.

[0350] In another aspect, the invention provides a method of treating
disorders associated with TACE, aggrecanase, TNF-α, MMPs, ADAMs or
any combination thereof, said method comprising administering to a
patient in need of such treatment an effective amount of at least one
compound of Formulae (I)-(IX).

[0351] In another aspect, the invention provides a use of a compound of
Formulae (I)-(IX) for the manufacture of a medicament to treat disorders
associated with TACE, aggrecanase, TNF-α, MMPs, ADAMs or any
combination thereof.

[0353] In another aspect, the invention provides a method of preparing a
pharmaceutical composition for treating the disorders associated with
TACE, aggrecanase, TNF-α, MMPs, ADAMs or any combination thereof,
said method comprising bringing into intimate contact at least one
compound of Formulae (I)-(IX) and at least one pharmaceutically
acceptable carrier.

[0354] In another aspect, the invention provides a compound of Formulae
(I)-(IX) exhibiting TACE, TNF-α, MMPs, ADAMs or any combination
thereof inhibitory activity, including enantiomers, stereoisomers and
tautomers of said compound, and pharmaceutically acceptable salts,
solvates, or esters of said compound, said compound being selected from
the compounds of structures listed in Table 1 set forth below.

[0355] In another aspect, the invention provides a pharmaceutical
composition for treating disorders associated with TACE, aggrecanase,
TNF-α, MMP, ADAM or any combination thereof in a patient
comprising, administering to the patient in need of such treatment a
therapeutically effective amount of at least one compound of Formulae
(I)-(IX) or a pharmaceutically acceptable salt, solvate, ester, or isomer
thereof.

[0356] In another aspect, the invention provides a compound of Formulae
(I)-(IX) in purified form.

[0357] In another aspect, the invention provides a method of treating a
condition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or
any combination thereof in a patient comprising: administering to the
patient in need of such treatment a therapeutically effective amount of
at least one compound of Formulae (I)-(IX) or a pharmaceutically
acceptable salt, solvate, ester or isomer thereof.

[0358] In another aspect, the invention provides a method of treating a
condition or disease selected from the group consisting of rheumatoid
arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration,
solid tumor growth and tumor invasion by secondary metastases,
neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and
psoriasis in a patient, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof.

[0359] In another aspect, the invention provides a method of treating a
condition or disease selected from the group consisting of fever,
cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia,
alcoholism, acute phase response, acute infection, shock, graft versus
host reaction, autoimmune disease and HIV infection in a patient
comprising administering to the patient in need of such treatment a
therapeutically effective amount of at least one compound of Formulae
(I)-(IX) or a pharmaceutically acceptable salt, solvate, ester, or isomer
thereof.

[0361] In another aspect, the invention provides a method of treating a
condition or disease selected from the group consisting of rheumatoid
arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis,
Crohn's disease, and ulcerative colitis, comprising: administering to a
patient in need of such treatment a therapeutically effective amount of
at least one compound of Formulae (I)-(IX) or a pharmaceutically
acceptable salt, solvate, ester or isomer thereof.

[0362] In another aspect, the invention provides a method of treating
rheumatoid arthritis, psoriasis, or inflammatory bowel disease (e.g.,
Crohn's disease or ulcerative colitis) comprising: administering to a
patient in need of such treatment a therapeutically effective amount of
at least one compound of Formulae (I)-(IX) or a pharmaceutically
acceptable salt, solvate, ester or isomer thereof.

[0363] In another aspect, the invention provides a method of treating a
condition or disease associated with COPD, comprising: administering to
the patient in need of such treatment a therapeutically effective amount
of at least one compound of Formulae (I)-(IX) or a pharmaceutically
acceptable salt, solvate, ester or isomer thereof.

[0364] In another aspect, the invention provides a method of treating a
condition or disease associated with rheumatoid arthritis, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester, or isomer thereof.

[0365] In another aspect, the invention provides a method of treating a
condition or disease associated with Crohn's disease, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof.

[0366] In another aspect, the invention provides a method of treating a
condition or disease associated with psoriasis, comprising: administering
to the patient in need of such treatment a therapeutically effective
amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester, or isomer thereof. In
specific embodiments, the therapeutically effective amount of the at
least one compound of Formulae (I)-(IX) or a pharmaceutically acceptable
salt, solvate, ester, or isomer thereof is topically administered to the
patient in need of treatment for psoriasis.

[0367] In another aspect, the invention provides a method of treating a
condition or disease associated with ankylosing spondylitis, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof.

[0368] In another aspect, the invention provides a method of treating a
condition or disease associated with sciatica, comprising: administering
to the patient in need of such treatment a therapeutically effective
amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof.

[0369] In another aspect, the invention provides a method of treating a
condition or disease associated with complex regional pain syndrome,
comprising: administering to the patient in need of such treatment a
therapeutically effective amount of at least one compound of Formulae
(I)-(IX) or a pharmaceutically acceptable salt, solvate, ester, or isomer
thereof.

[0370] In another aspect, the invention provides a method of treating a
condition or disease associated with psoriatic arthritis, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX), or a
pharmaceutically acceptable salt, solvate, ester, or isomer thereof.

[0371] In another aspect, the invention provides a method of treating a
condition or disease associated with multiple sclerosis, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester or isomer thereof, in
combination with a compound selected from the group consisting of
Avonex®, Betaseron, Copaxone or other compounds indicated for the
treatment of multiple sclerosis.

[0372] Additionally, a compound of the present invention may be
co-administered or used in combination with disease-modifying
antirheumatic drugs (DMARDS) such as methotrexate, azathioprine,
leflunomide, pencillinamine, gold salts, mycophenolate mofetil,
cyclophosphamide and other similar drugs. They may also be
co-administered with or used in combination with non-steroidal
anti-inflammatory drugs (NSAIDs) such as piroxicam, naproxen,
indomethacin, ibuprofen and the like; cycloxygenase-2 selective (COX-2)
inhibitors such as Vioxx® and Celebrex®; immunosuppressives such
as steroids, cyclosporin, Tacrolimus, rapamycin and the like; biological
response modifiers (BRMs) such as Enbrel®, Remicade®, IL-1
antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the
like; and other anti-inflammatory agents such as p38 kinase inhibitors,
PDE4 inhibitors, other chemically different TACE inhibitors, chemokine
receptor antagonists, Thalidomide and other small molecule inhibitors of
pro-inflammatory cytokine production.

[0373] Also, a compound of the present invention may be co-administered or
used in combination with an H1 antagonist for the treatment of seasonal
allergic rhinitis and/or asthma. Suitable H1 antagonists may be, for
example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.

[0374] In another aspect, the invention provides a method of treating a
condition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or
any combination thereof in a patient comprising: administering to the
patient in need of such treatment a therapeutically effective amount of
at least one compound of Formulae (I)-(IX) or a pharmaceutically
acceptable salt, solvate or isomer thereof in combination with a
therapeutically effective amount of at least one medicament selected from
the group consisting of disease modifying anti-rheumatic drugs (DMARDS),
NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives,
biological response modifiers (BRMs), anti-inflammatory agents and H1
antagonists.

[0375] In another aspect, the invention provides a method of treating a
condition or disease selected from the group consisting of rheumatoid
arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration,
solid tumor growth and tumor invasion by secondary metastases,
neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and
psoriasis in a patient, comprising:

administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester, or isomer thereof in
combination with a therapeutically effective amount of at least one
medicament selected from the group consisting of DMARDS, NSAIDs, COX-2
inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory
agents and H1 antagonists.

[0376] In another aspect, the invention provides a method of treating a
condition or disease selected from the group consisting of fever,
cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia,
alcoholism, acute phase response, acute infection, shock, graft versus
host reaction, autoimmune disease, and HIV in a patient, comprising
administering to the patient in need of such treatment a therapeutically
effective amount of at least one compound of Formulae (I)-(IX) or a
pharmaceutically acceptable salt, solvate, ester, or isomer thereof in
combination with a therapeutically effective amount of at least one
medicament selected from the group consisting of DMARDS, NSAIDs, COX-2
inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory
agents and H1 antagonists.

[0378] In another aspect, the invention provides a method for treating RA
comprising administering a compound of the Formulae (I)-(IX) in
combination with compound selected from the class consisting of a COX-2
inhibitor e.g. Celebrex® or Vioxx®; a COX-1 inhibitor, e.g.,
Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; a
steroid e.g. β-methasone; and anti-TNF-α compound, e.g.
Enbrei® or Remicade®; a PDE IV inhibitor, or other classes of
compounds indicated for the treatment of RA.

[0379] In another aspect, the invention provides a method for treating
multiple sclerosis comprising administering a compound of the Formulae
(I)-(IX) in combination with a compound selected from the group
consisting of Avonex®, Betaseron, Copaxone or other compounds
indicated for the treatment of multiple sclerosis.

[0380] TACE activity is determined by a kinetic assay measuring the rate
of increase in fluorescent intensity generated by TACE catalyzed cleavage
of an internally quenched peptide substrate (SPDL-3). The purified
catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477
with two mutations (S266A and N452Q) and a 6×His tail) is used in
the assay. It is purified from the baculovirus/Hi5 cells expression
system using affinity chromatography. The substrate SPDL-3 is an
internally quenched peptide
(MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its
sequence derived from the pro-TNFα cleavage site. MCA is
(7-Methoxycoumarin-4-yl)acetyl. Dpa is
N-3-(2,4-Dinitrophenyl)-L-2,3-diaminopropionyl.

[0381] A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM
CaCl2, 100 μM ZnCl2, 2% DMSO, 0.04% Methylcellulose, 30
μM SPDL-3, 70 pM rhTACEc and a test compound. RhTACEc is pre-incubated
with the test compound for 90 min. at 25° C. Reaction is started
by addition of the substrate. The fluorescent intensity (excitation at
320 nm, emission at 405 nm) was measured every 45 seconds for 30 min.
using a fluorospectrometer (GEMINI XS, Molecular Devices). Rate of
enzymatic reaction is shown as Units per second. Effect of a test
compound is shown as % of TACE activity in the absence of the compound.

[0382] The compounds' ability to inhibit TACE activity can also be
determined in human whole blood using the assay conditions described in
Example 35 below.

[0383] The pharmaceutical compositions containing the active ingredient
may be in a form suitable for oral use, for example, as tablets,
lozenges, aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs. Compositions
intended for oral use may be prepared according to any method known to
the art for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid; binding
agents, for example starch, gelatin or acacia, and lubricating agents,
for example magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract and thereby
provide a sustained action over a longer period. For example, a time
delay material such as glyceryl monostearate or glyceryl distearate may
be employed. They may also be coated by the technique described in U.S.
Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic
tablets for controlled release.

[0384] The term pharmaceutical composition is also intended to encompass
both the bulk composition and individual dosage units comprised of more
than one (e.g., two) pharmaceutically active agents such as, for example,
a compound of the present invention and an additional agent selected from
the lists of the additional agents described herein, along with any
pharmaceutically inactive excipients. The bulk composition and each
individual dosage unit can contain fixed amounts of the afore-said "more
than one pharmaceutically active agents". The bulk composition is
material that has not yet been formed into individual dosage units. An
illustrative dosage unit is an oral dosage unit such as tablets, pills
and the like. Similarly, the herein-described method of treating a
patient by administering a pharmaceutical composition of the present
invention is also intended to encompass the administration of the
afore-said bulk composition and individual dosage units.

[0385] Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredients is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
a soft gelatin capsules where in the active ingredient is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive
oil.

[0386] Aqueous suspensions contain the active material in admixture with
excipients suitable for the manufacture of aqueous suspensions. Such
excipients are suspending agents, for example, sodium
carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,
sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene oxide with
fatty acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethylene-oxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example, polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives, for example,
ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.

[0387] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example, arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The
oily suspensions may contain a thickening agent, for example, beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.

[0388] Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water provide the active ingredient
in admixture with a dispersing or wetting agent, suspending agent and one
or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients, e.g., sweetening, flavoring and coloring agents,
may also be present.

[0389] The pharmaceutical compositions of the invention may also be in the
form of an oil-in-water emulsion. The oily phase may be a vegetable oil,
e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin
or mixtures of these. Suitable emulsifying agents may be
naturally-occurring phosphatides, e.g., soy beans, lecithin, and esters
or partial esters derived from fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, and condensation products of the said
partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.

[0390] Syrups and elixirs may be formulated with sweetening agents, for
example, glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and flavoring
and coloring agents.

[0391] The pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleagenous suspension. This suspension may be
formulated according to the known art using those suitable dispersing or
wetting agents and suspending agents which have been mentioned above. The
sterile injectable preparation may also be a sterile injectable solution
or suspension in a non-toxic parenterally-acceptable diluent or solvent,
e.g., as a solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and isotonic
sodium chloride solution. In addition, sterile fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.

[0392] Compounds of the invention may also be administered in the form of
suppositories for rectal administration of the drug. The compositions can
be prepared by mixing the drug with a suitable non-irritating excipient
which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the drug.
Such materials are cocoa butter and polyethylene glycols.

[0393] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compounds of the invention are
employed. (For purposes of this application, topical application shall
include mouthwashes and gargles.)

[0394] The compounds for the present invention can be administered in the
intranasal form via topical use of suitable intranasal vehicles, or via
transdermal routes, using those forms of transdermal skin patches well
known to those of ordinary skill in the art. To be administered in the
form of a transdermal delivery system, the dosage administration will, of
course, be continuous rather than intermittent throughout the dosage
regimen. Compounds of the present invention may also be delivered as a
suppository employing bases such as cocoa butter, glycerinated gelatin,
hydrogenated vegetable oils, mixtures of polyethylene glycols of various
molecular weights and fatty acid esters of polyethylene glycol.

[0395] The dosage regimen utilizing the compounds of the present invention
is selected in accordance with a variety of factors including type,
species, weight, sex and medical condition of the patient; the severity
of the condition to be treated; the route of administration; the renal
and hepatic function of the patient; and the particular compound thereof
employed. A physician or veterinarian of ordinary skill can readily
determine and prescribe the effective amount of the drug required to
prevent, counter, arrest or reverse the progress of the condition.
Optimal precision in achieving concentration of drug within the range
that yields efficacy without toxicity requires a regimen based on the
kinetics of the drug's availability to target sites. This involves a
consideration of the distribution, equilibrium, and elimination of a
drug. Preferably, doses of the compound of Formulae (I)-(iX) useful in
the method of the present invention range from 0.01 to 1000 mg per day.
More preferably, dosages range from 0.1 to 1000 mg/day. Most preferably,
dosages range from 0.1 to 500 mg/day. For oral administration, the
compositions are preferably provided in the form of tablets containing
0.01 to 1000 milligrams of the active ingredient, particularly 0.01,
0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500
milligrams of the active ingredient for the symptomatic adjustment of the
dosage to the patient to be treated. An effective amount of the drug is
ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about
50 mg/kg of body weight per day. The range is more particularly from
about 0.001 mg/kg to 1 mg/kg of body weight per day.

[0396] Advantageously, the active agent of the present invention may be
administered in a single daily dose, or the total daily dosage may be
administered in dividend doses of two, three or four time daily.

[0397] The amount of active ingredient that may be combined with the
carrier materials to produce single dosage form will vary depending upon
the host treated and the particular mode of administration.

[0398] It will be understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors including
the age, body weight, general health, sex, diet, time of administration,
route or administration, rate of excretion, drug combination and the
severity of the particular disease undergoing therapy.

[0399] The compounds of the invention may be produced by processes known
to those skilled in the art and as shown in the following reaction
schemes and in the preparations and examples described below.

EXAMPLES

General

[0400] The following abbreviations are used in the procedures and schemes:

[0424] Alkylation of acetylene 10 with a suitable A-1 compound yields the
quaternary protected amino acid derivative A-2. Compound A-2 may be
either cyclized into hydantoin A-4 or deprotected to acetylene A-3.
Introduction of the (hetero)aryl ring is readily accomplished via a
Sonogashira reaction with a (hetero)arylhalide to afford intermediates
A-5 or A-6. Compound A-5 is converted to A-6 by treatment with 7M ammonia
in methanol solution at 80° C. in a sealed bottle. Compound A-6
may be converted to a pro-drug A-7 by treatment with a suitable
alkylating agent.

##STR00049## ##STR00050##

[0425] Alkylation of acetylene 10 with a suitable A-1 compound yields the
quaternary protected amino acid derivative A-2. Compound A-2 may be
either cyclized into hydantoin A-4 or deprotected to acetylene A-3.
Conversion of the acetylene moiety to a fused biaryl ring is readily
accomplished via a Sonogashira reaction with a (hetero)arylhalide to
afford intermediates B-5 or B-6. Compound B-5 is converted to B-6 by
treatment with 7M ammonia in methanol solution at 80° C. in a
sealed bottle. Compound B-6 may be converted to a pro-drug B-7 by
treatment with a suitable alkylating agent.

[0429] Compound 3 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in
MeOH (150 mL) and stirred in a sealed pressure flask at 60° C.
overnight. The reaction mixture was cooled and the solvent was removed
under reduced pressure. The residue was suspended in ethyl acetate and
stirred for 30 minutes. The solids were filtered and dissolved in
methylene chloride. The organic layer was washed with water, dried over
sodium sulfate, and concentrated to provide the desired product 4 (13.5
g, 67%).

[0434] Compound 7 (32.0 g, 214 mmol) was dissolved in MeOH (200 mL) and
cooled in an ice bath. Concentrated sulfuric acid (8 mL) was added
dropwise and the reaction was stirred overnight. The reaction mixture was
diluted with ethyl acetate and water. The organic layer was washed with
brine, dried over sodium sulfate, and concentrated to provide compound 8
that was used without purification (27.0 g, 71%).

Part C:

[0435] Compound 8 (27.0 g, 152 mmol) was dissolved in carbon tetrachloride
(700 mL). Phosphorus pentachloride (50 g, 240 mmol) was added and the
suspension was stirred for 18 hours (solution became clear over time).
The solvent was removed under reduced pressure and the residue was
stirred in petroleum ether (500 mL) overnight. The solids were filtered
to provide compound 9 with no need for purification (26.5 g, 96%).
Trituration step was repeated if mass yield was too high.

[0438] The two isomers were separated using a chiral OD column. One gram
of material was injected into the column and the two peaks were separated
by using a solvent mixture of 85% hexanes/ethanol. The second isomer was
the desired compound 12 (400 mg, 80%).

Part G:

[0439] Compound 12 (8.0 g, 19.1 mmol) was dissolved in THF (250 mL) and
cooled to 0° C. Tetrabutylammonium fluoride (1 M in THF, 22.9 mL,
22.9 mmol) was added dropwise and the reaction was stirred for 1 hour at
room temperature. The reaction mixture was diluted with ethyl acetate and
water. The organic layer was washed with water, saturated sodium
bicarbonate, brine, dried over sodium sulfate and concentrated to provide
compound 13 (5.8 g, 88%). The product was used without purification.

[0443] Compound 15 (50.8 g, 298.65 mmol) and 16 (55.55 g, 313.58 mmol)
were pre-mixed as solids and added to a concentrated sulfuric acid (150
mL) at 10° C. The reaction mixture was stirred at 10-15° C.
for 2-3 hours. The reaction mixture was slowly added to ice water (800
mL) with good stirring. The reaction flask was rinsed with concentrated
sulfuric acid and wash was added to the ice water. The solid was
collected by filtration, washed with water (2×) and dried at
50° C. under vacuum to afford compound 17 (>100% by weight).

Part B:

[0444] To a solution of compound 17 (298.65 mmol) in DMF (1 L) was added
sequentially cesium carbonate (127 g, 388.24 mmol) and methyl iodide
(22.3 mL, 358.38 mmol). The reaction was stirred overnight at room
temperature. The reaction mixture was diluted with water (800 ml) and
ethyl acetate (800 mL) and the layers were separated. The aqueous layer
was extracted with ethyl acetate (500 mL). The combined organic layers
were washed with brine, dried over sodium sulfate and concentrated in
vacuum. The crude reaction product was used without further purification.

Part C:

[0445] The crude product 18 was dissolved in methanol (1 L) and hydrazine
hydrate (29 ml, 597.3 mmol) was added. The reaction mixture was stirred
with a mechanical stirrer and heated to reflux for 3 hours. The reaction
mixture was initially a suspension which cleared upon heating. As the
reaction progressed a precipitate formed. The reaction mixture was cooled
and the precipitate was collected by filtration. The solids were washed
with methanol and the combined filtrate was reduced in volume to
approximately 300 mL. The additional precipitate was collected by
filtration and combined with the above solids. The solids were stirred
with potassium carbonate solution (1 M, 200 mL) for 15 minutes and
filtered. This washing process was repeated with another portion of
potassium carbonate solution (1M, 150 ml). The solids were then washed
with hydrochloric acid (2 M, 150 ml) for 15 minutes and filtered. This
washing process was repeated with another portion of hydrochloric acid
(1M, 150 ml) and the solid was rinsed with water. The potassium carbonate
solution was extracted with ethyl acetate twice. The ethyl acetate washes
were combined with the methanol filtrate, washed with brine, dried over
sodium sulfate, and concentrated. The residue was washed with potassium
carbonate solution (1 M, 20 mL) and hydrochloric acid (2 M, 20 mL). The
additional solid was rinsed with water and combined with above solid. It
was dried under vacuum at 50° C. for overnight to give compound 19
(47.87 g, 88.5% from compound 15).

Part D:

[0446] To a 3 L three neck flask was added compound 19 (61.07 g, 337.11
mmol), sodium t-butoxide (38.9 g, 404.5 mmol, 1.2 eq.), and DMPU (1500
mL). The suspension was stirred with a mechanic stirrer and gently warmed
with a heat gun until a clear solution appeared. The solution was cooled
to 0° C. and chloromethyl pivalate was added slowly with a
syringe. The reaction mixture was stirred at 0° C. for three
hours, diluted with H2O (1.5 L) and EtOAc (1.5 L), and the layers
were separated. The organic layer was washed with H2O (500
mL×4), brine (500 mL), dried over sodium sulfate, and concentrated
in vacuum. The product was purified by silica gel chromatography
(Hexane/EtOAc: 2:1 to 1:1 to 0:1) to afford compound 20 (77.98 g, 78.3%)

Part E:

[0447] Compound 20 (70.97 g, 240.32 mmol) was dissolved in anhydrous
CH2Cl2 (1 L). The solution was cooled to 0° C. and TMSBr
(37.3 mL, 288.39 mmol) was added via syringe. The reaction mixture was
stirred at 0° C. for two hours and concentrated in vacuum at
25° C. The residue was stirred with Hexane (500 mL) for 15 min,
filtered, and rinsed with hexane (60 mL×2). The Hexane filtrate was
concentrated in volume to approximately 100 mL and the additional solid
was filtered, rinsed with hexane (10 mL×2), and combined with above
solid. The solid was dried under vacuum for overnight to give compound 21
(64.81 g, 98.4%).

Part F:

[0448] To a flamed dried flask was added compound 21 (1.13 g, 4.11 mmol),
compound 10 (1.0 g, 4.11 mmol), and anhydrous THF (25 mL). The solution
was cooled to -78° C. and LiHMDS (8.63 mL, 8.63 mmol) was added
via syringe. The reaction mixture was stirred at -78° C. for two
hours, diluted with saturated NH4Cl solution (30 mL) and EtOAc (50
mL). After warming up to room temperature, the aqueous layer was
separated and extracted with EtOAc (20 mL) once. The organic layers were
combined and TBAF (1 M in THF, 7 mL, 7 mmol) was added. The solution was
stirred at 25° C. for 10 min, washed with water (50 mL), brine (50
mL), dried over sodium sulfate, and concentrated in vacuum. The product
was purified by silica gel chromatography (Hexane/EtOAc: 2:1 to 1:1 to
0:1) to afford the racemate of compound 22 (891 mg, 59.5%)

[0464] The two isomers were separated using a chiral normal phase OD
column. 107 was injected into the column and the two peaks were separated
using a solvent mixture of 85% hexanes/ethanol. Isomer 108 (40.5 mg, 70%)
and 109 (39.9 mg, 69%) were isolated.

[0472] To a pressure bottle was added compound 17001(314 mg, 1.0 mmol),
compound 1700J (294 mg, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05
mmol), acetonitrile (5 mL) and potassium carbonate (5 mL, 1 N aq.). The
reaction mixture was subjected to vacuum, and the purged with nitrogen
for three times and stirred at 80° C. overnight. The reaction
mixture was diluted with water (30 mL) and extracted with EtOAc
(3×20 mL). The organic layers were combined and washed with brine,
dried over sodium sulfate, and concentrated to dryness. The residue was
purified by silica gel chromatography (Hexane/EtOAc:1:3) to afford 1700H,
(110 mg, 43%).

Part B:

[0473] A mixture of compound 1700H (56 mg, 0.022 mmol) and AlCl3 (70
mg, 0.055 mmol) was suspended in CH2Cl2 (5 mL). The reaction
mixture was refluxed overnight. After cooling, the solvent was
evaporated. The residue was mixed with water (10 mL) and extracted with
EtOAc (10 mL×3). The organic layers were combined and washed with
brine. The resulting organic layer was dried over sodium sulfate and
concentrated to give compound 1700G. The compound was used in the next
step without further purification.

Example 13

##STR00065##

[0474] Part A:

[0475] Compound 1700A (800 mg, 3.26 mmol), compound 1700K (1.46 mL, 9.79
mmol), Pd(PPh3)2Cl2 (183 mg, 0.26 mmol). CuI (93 mg, 4.9
mmol), and diisopropylamine (1 mL) were dissolved in DMF and stirred at
80° C. overnight. The solvent was removed under reduced pressure
and the residue was diluted with CH2Cl2 (50 mL), washed by
water and brine, and dried over sodium sulfate. The mixture was filtered.
The filtrate was concentrated and the residue was purified by column
chromatography (5% of 7N Ammonia in MeOH solution in CH2Cl2) to
give 1700B (500 mg, 75%).

Part B:

[0476] Compound 1700B (500 mg, 2.44 mmol) was added to DMPU (20 mL) and
heated with a heat gun until all the material was dissolved. The mixture
was then cooled down to room temperature. Sodium t-butoxide (281 mg, 2.92
mmol) was added and the mixture was stirred at room temperature for 5
hours. Chloromethylpivalate (0.42 mL, 2.92 mmol) was added dropwise and
the mixture was stirred at room temperature for 3 hours. The reaction
mixture was poured into 150 ml water. The resulting solid was then
filtered and collected to give 1700C (560 mg, 72%).

Part C:

[0477] Compound 1700C (560 mg, 1.75 mmol) was dissolved in methylene
chloride (10 mL) and cooled in an ice bath. Bromotrimethylsilane (0.3 mL,
2.08 mmol) was added dropwise and the mixture was stirred in the ice bath
for 30 minutes followed by 2 hours at room temperature. The reaction
mixture was concentrated and re-dissolved in methylene chloride (2 mL).
Hexanes (8 mL) was added and the solids were filtered to provide the
desired product 1700D (360 mg, 70%).

[0479] Compound 1700E (360 mg, 0.927 mmol) in 7 M ammonia in methanol (10
mL) was heated to 85° C. in a pressure bottle overnight. TLC
indicated that the reaction was not complete. Therefore, the solvent was
evaporated and the residue was dissolved in 7M ammonia in methanol (10
mL) and heated to 85° C. in a pressure bottle for overnight. The
reaction mixture was concentrated. The residue was washed with ether and
filtered. The solid was collected to afford 1700F (150 mg, 50%) which was
used in the next step without further purification.

[0482] Compound 1701A (1.8 g, 4.59 mmol) and AlCl3 (1.8 g, 13.50
mmol) were stirred in methylene chloride in a sealed tube at 75°
C. overnight. After cooling, the reaction mixture was taken up in ethyl
acetate and extracted with water. The aquous layer was extracted with
ethyl acetate 3 times. The combined organic layers were dried with
Na2SO4 and then concentrated to dryness. The crude material
which was 1701B (1.6 g, 92%) was used without further purification.

Part B:

[0483] Compound 1701B (300 mg, 0.79 mmol) was dissolved in ammonium
hydroxide (9 mL) and stirred in ice bath to make mixture 1. Iodine (180
mg, 0.63 mmol) and KI (421 mg, 2.54 mmol) were dissolved in H2O (3
mL) and this mixture was added dropwise to mixture 1. After addition, the
ice bath was removed and the reaction mixture was stirred at room
temperature for 2 h. After the reaction was terminated, the solvent was
removed. The crude material was purified with ISCO reverse phase column
and eluted with actonitrile-water to give 1701C (100 mg, 25%).

[0488] Compound 1705D (240 gm, 0.56 mmol) was dissolved in methanol (10
mL) and HCl (20 mL, 4N in dioxane) was added and the reaction mixture was
stirred at room temperature two and half days. The mass spectrum of the
reaction mixture still showed the presence of starting material. Solvents
were removed and HCl (50 mL, 6N in H2O) and methanol (10 mL) were
added and the mixture was stirred at room temperature overnight. Solvents
were removed to afford compound 1705E (140 mg, 99%) which was used
without further purification.

[0496] Compound 1120A was converted to 1120B using the procedure of
Foccella, A.; Bizzarro, F. and Exon, C. Syn Comm 1991, 21, 2165. The
crude product was purified via reverse phase chromatography on a C-18
column using a 15%-80% CH3CN/H2O gradient with 0.1% formic acid
added to each component of the mobile phase. The gradient was stopped
temporarily at 35% CH3CN while the main peak came off of the column
to give 22 mg of impure product. This material was purified via reverse
phase HPLC on a C-18 column using a 5%-50% CH3CN/H2O gradient
with 0.1% formic acid added to each component of the mobile phase.
Compound 1120B was obtained as a white solid. LCMS calcd. 368.1 obsd
369.2.

Example 19

##STR00071##

[0498] 2,4-Difluoro-3-methoxy-benzoic acid was converted to compound 1140F
using a sequence of reactions and a set of procedures similar to those
described in Example 4.

[0505] Compound 1140F was separated into its enantiomers via chiral HPLC.
Compound 1140F (0.5 gram) was dissolved in 5 mL of 4:6 CHCl3:MeOH
and injected onto a preparative ChiralCel OD HPLC column from Chiral
Technologies. The detector was set at 237 nm. The mobile phase was 95:5
hexanes:absolute ethanol at a flow rate of 50 mL/min.

[0509] Compound 1150B (41 mg, 0.064 mmol) was dissolved in 2 mL of MeOH. A
solution of 4N HCl in dioxane was added (3 mL). The reaction mixture was
stirred for 4 h at it then concentrated to dryness. The product was
dissolved in a minimum amount of MeOH. EtOAc was added, causing a
precipitate to form. The mixture was placed in a centrifuge, to spin down
the precipitate. The solution was removed via pipet. The solid was washed
with EtOAc then dried under vacuum to give 30 mg of compound 1150. LCMS
calcd 538.14 obsd 539.3.

Example 21

##STR00073##

[0510] Part A

[0511] Compound 1150A was converted to 1160 using a procedure similar to
that described in Example 7. LRMS calcd 428.09 obsd 429.2.

[0525] A solution of Compound 2218B (96 mg, 0.38 mmol) in DCE (5 mL) was
treated with anhydrous aluminum chloride (126 mg, 0.94 mmol) in a
pressure vessel. The vessel was capped and the reaction mixture was
heated at reflux for 18 h. The reaction mixture was allowed to cool to rt
and was concentrated under reduced pressure. The resulting residue was
partitioned in EtOAc (˜100 mL) and water (˜100 mL). The
aqueous layer was separated and extracted further with EtOAc
(3×˜25 mL). The combined organic phases were washed with
brine (50 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to afford 104 mg of crude product as
a yellow solid. Mass calculated for formula
C8H681BrN3O 241.0, observed m/z 241.9 [M+H].sup.+.

[0529] Solid N-chlorosuccinimide (0.722 g, 5.39 mmol) was added to a
stirred solution of oxime (Compound 2224B; 1.072 g, 5.39 mmol) in dry DMF
(15 mL). The reaction mixture was stirred at rt for 18 h. The reaction
mixture was diluted with Et2O (150 mL) and was washed sequentially
with water (3×50 mL) and brine (˜50 mL). The organic layer
was dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to give a pale yellow solid. Purification of the solid
by sgc (40 g silica gel cartridge; 5-25% EtOAc-hexanes gradient) gave 973
mg (77% yield) of the desired product, Compound 2224C, as a white solid.

Part C

[0530] Methyl-n-propylamine (151 mg, 2.56 mmol) was added to a solution of
oximyl chloride (Compound 2224C, 300 mg, 1.28 mmol) in CH2Cl2
(8 mL) and the resulting mixture was stirred overnight at rt. Evaporation
of the solvent gave a residue that was purified by sgc (1-10%
MeOH/NH3 in CH2Cl2 gradient) to afford 215 mg (62% yield)
of the desired product, Compound 2224D.

[0544] To a 5 mL flask was added compound 13040 (65 mg, 0.11 mmol),
2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (35 mg,
0.16 mmol), Pd(dppf)2Cl2 (5 mg). The flask was subjected to
vacuum and flushed with N2 three times. K2CO3 (1M, 0.5 mL,
0.5 mmol) and CH3CN were added. The solution was stirred at
80° C. overnight. After the flask had cooled, water and EtOAc were
added. The organic layer was separated, washed with brine, dried over
Na2SO4, and concentrated. The product was purified by SiO2
chromatography (MeOH/DCM: 1% to 5%) to give compound 1304E.

Part E

[0545] Compound 1304E obtained in Part D was dissolved in MeOH (2 mL) in a
15 mL pressure tube. HCl (4M in dioxane, 2 mL) was added. The tube was
capped and stirred at 90° C. for overnight. After cooling down,
the solvent was removed and residue was dissolved in MeOH (3 ml) and
DIPEA (0.5 mL) was added. The solution was stirred at RT for three hours.
The solvent was removed and the product was purified by C18
chromatography (CH3CN/H2O, 5% to 90%, with 0.1% HCO2H) to
give compound 1304 (23.5 mg, 43.2%).

[0548] Compound 2210B (600 mg, 2.75 mmol) was dissolved in
NH3--H2O (37%, 40 mL). Heating may be needed to make a clear
solution. A solution of I2 (628 mg, 2.47 mmol) and KI (1.64 g, 9.88
mmol) in water (5 mL) was added dropwise. The solution was stirred at
25° C. for 1 hour. The solution was concentrated to half of its
original volume, adjusting the pH to 2˜4 with HCl (2N). The solid
was collected by filtration, washed with water, dried under vacuum for
overnight to give compound 2210C (805 mg, 85.1%)

[0549] Compounds 2210, 2211, 2214, 2216, and 2223 were prepared by the
methods described in Example 29 and Example 6.

Example 30

##STR00085##

[0550] Part A

[0551] Compound 2213A (800 mg, 3.67 mmol) was suspended in anhydrous THF
(40 mL) and cooled to 0° C. Red-AI (3.2 M, 9.2 mL, 29.4 mmol) was
added dropwise. After the addition was completed, the solution was heated
to 85° C. for 2 hours. It was then cooled to 0° C. and
quenched with water. Organic solvent was removed by rotary evaporator.
NaOH (1N) was added to adjust the pH to about 7. EtOAc was added and the
organic layer was separated. The aqueous layer was extracted with EtOAc
twice. The EtOAc layers were combined and concentrated. The product was
purified by SiO2 chromatography to give compound 2213C (539.5 mg,
72.1%).

Part B

[0552] Compound 2213C was prepared by the same method as described in part
B of example 29.

[0553] Compounds 2213 and 2215 were prepared by the methods described in
Example 30 and Example 6.

Example 31

##STR00086##

[0554] Part A

[0555] Compound 2237A (300 mg, 0.73 mmol) was dissolved in DMF (5 ml).
Cs2CO3 (476 mg, 1.45 mmol) and MeI (0.5 mL) were added. The
solution was stirred at RT for overnight. Water and EtOAc were added. The
organic layer was separated, washed with brine, dried over
Na2SO4, and concentrated. The product was purified by SiO2
chromatography (Hexane/EtOAc 1:0 to 1:1) to give compound 2237B (295 mg,
95.1%).

Part B

[0556] Compound 2237B (140 mg, 0.33 mmol) was stirred with NH3/MeOH
(7N, 3 mL) in a pressure tube at 110° C. for three days. After
cooling down, the solvent was removed by rotary evaporator and the
product was purified by sgc (DCM/MeOH/NH3--H2O: 20; 1:0.1 to
10:1:0.1) to give compound 2237C (67 mg, 49%).

[0557] Compound 2237 were prepared by the methods described in Example 31
and Example 6.

Example 32

##STR00087##

[0558] Part A

[0559] Compound 2238A was prepared by the method described in Example 6.

[0563] Compound 2239 were prepared by the methods described in Example 33
and Example 6.

Example 34

##STR00089##

[0564] Deuterated 2200 (2242)

[0565] Compound 2242 is prepared following the procedure of Example 22.
Deuterated intermediate 14a is obtained from 6a following the procedures
described in Example 2 and Example 3. Compound 6a itself can be obtained
following the procedure in Example 1, starting from the known compound
1a-1. Compound 14a is reacted with intermediate 2200C-1 which is obtained
following the procedure in Example 22 by first converting commercially
available 2200A-1 to 2200 A4 following published procedures in the
following references: Garrett, Mark D.; Scott, Robin; Sheldrake, Gary N.;
Dalton, Howard; Goode, Paul. Organic & Biomolecular Chemistry (2006),
4(14), 2710-2715; Allen, C. F. H.; Thirtle, John R. USA. Organic
Syntheses (1946 John Wiley & Sons, Inc.; and Koch, Volker; Schnatterer,
Stefan. Synthesis (1990), (6), 497-8.

##STR00090##

Example 35

Assay for Inhibition of TNF-α Production from Human Whole Blood
(hWBA)

[0566] Human whole blood was diluted 1:1 with serum free medium (RPMI,
L-glutamine, Pen-Strep, HEPES) and incubated with a test compound in a
final volume of 360 μL for 1 h at 37° C. Forty microliters of
LPS (10 μg/mL) was then added. Supernatant was collected after 3.5 h
incubation and the concentration of TNF-α was determined by ELISA
(R&D Systems). The concentration of the test compound which inhibits 50%
of the amount of TNF-α from the control untreated control was
determined. The IC50 values for representative compounds of the
formulae (I)-(IX) are shown below in Tables A and B.

Example 36

Area Under the Curve Determinations of Plasma Levels in Rats (rrAUC)

[0567] To gain insight into the pharmacokinetic properties of the
compounds of formula (I), plasma levels of the compounds in rats were
determined according to the protocol described in Korfmacher, W. A.; Cox,
K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.; Broske, L.;
Prelusky, D.; Nomeir, A.; White, R. E. Rapid Commun. Mass Spectrom, 2001,
15, 335, Briefly, rats, after an overnight fast, were dosed orally with
the test compound at a dose of 10 mg/kg in a 5 mL/kg dose volume. Blood
was collected at 0.5, 1, 2, 3, 4, and 6 h post-dosing. Mass spectrometry
using high performance liquid chromatography was used to identify and
measure the concentrations of the test compounds in the plasma at the
various time points. The parent ion of each test compound was used to
identify and quantitate the compounds in plasma. The area under the curve
(AUC) data for representative compounds of the formulae (I)-(IX) are
shown below in in Tables A and B.

[0568] The following compounds were prepared using previously described
procedures:

[0569] It will be appreciated by those skilled in the art that changes
could be made to the embodiments described above without departing from
the broad inventive concept thereof. It is understood, therefore, that
this invention is not limited to the particular embodiments disclosed,
but it is intended to cover modifications that are within the spirit and
scope of the invention, as defined by the appended claims.

[0570] Each document referred to herein is incorporated by reference in
its entirety for all purposes.

Patent applications by Aneta Maria Kosinski, South Amboy, NJ US

Patent applications by Bandarpalle B. Shankar, Branchburg, NJ US

Patent applications by Brian J. Lavey, New Providence, NJ US

Patent applications by Dansu Li, Reading, MA US

Patent applications by De-Yi Yang, Morris Plains, NJ US

Patent applications by Guowei Zhou, Somerset, NJ US

Patent applications by Joseph A. Kozlowski, Princeton, NJ US

Patent applications by Judson E. Richard, Kittery, ME US

Patent applications by Kristen E. Rosner, Watertown, NJ US

Patent applications by Lei Chen, Roselle Park, NJ US

Patent applications by Ling Tong, Warren, NJ US

Patent applications by Luke Fire, Cambridge, MA US

Patent applications by Michael K.c. Wong, Somerset, NJ US

Patent applications by Razia K. Rizvi, Bloomfield, NJ US

Patent applications by Seong Heon Kim, Livington, NJ US

Patent applications by Wensheng Yu, Edison, NJ US

Patent applications by Schering Corporation

Patent applications in class Hetero ring is seven-membered consisting of two nitrogens and five carbon atoms

Patent applications in all subclasses Hetero ring is seven-membered consisting of two nitrogens and five carbon atoms